**The first lecture

Introductory lecture

Reading assignment: Chapter 1 and other material specifically referenced

What is life?

Fig. 3.1
showing a cell

If this were the first lecture for introductory biology, we would ask, "What is unique to life?" and we might argue that "Inside the cell is alive. Outside is not. The plasma membrane is thus the gate-keeper that separates the quick from the dead."(1) Then we would develop the following list:

#1. Life is very complex.
#2. Life has excitability.
#3. Life has development.
#4. Life utilizes metabolism.
#5. Life's processes are regulated by homeostasis
#6. Evolution is major unifying principle
#7. Reproduction is fundamental

In introductory biology (but not in physiology), we would concentrate on:
#1. Life is very complex and has complex macromolecules (DNA, RNA, protein).
#3. Life has development, growth, form
#6. Evolution is major unifying principle, and present-day organisms have an unbroken ancestry of 3 1/2 billion yrs
#7. Reproduction is fundamental causing us to define "survival" in biology in terms of reproduction and production of fertile offspring.

What is Physiology?

In Physiology, we will concentrate on:

#2. Life has excitability, movement and responsiveness (irritability, sensitivity)

Figure
Excitability - Copy of a page from a mathematically oriented text from 1971 text (2)

In the mid-1800's, it might be hard to distinguish a physiologist and a physicist, and Helmholtz made contributions in both disciplines.

Figure
Nervous system -Copy of a page from the book I used when I took physiology in 1969 (3), by Sir Bernard Katz, (Nobel Prize, 1970), one of many neuroscientists to win the Nobel Prize in Physiology and Medicine

#4. Life utilizes metabolism, and we will concentrate on:

Catabolic processes, for the production and delivery of energy. (However, we will not dwell on the bioenergetics coverage as much as "BL A302 Cellular Biochemistry and Molecular Biology.")

and

(to a lesser extent) Anabolic processes, involving build-up. (You have heard the term "anabolic steroids," such as testosterone and drugs of abuse among athletes.)

Perhaps, foremost, in Physiology, we will concentrate on
#5. Life's processes are regulated by homeostasis

Homeostasis: the thermostat

TRANSPARENCY (Review figure from introductory biology) A fundamental example is the thermostat.
Negative feedback is sometimes referred to as a servo mechanism.
The thermostat works by negative feedback.
In house, "effector" would be furnace heat

Heat (energy) is what changes temperature.
1 calorie raises temperature of 1 ml of water 1 degree C
(the "calories" you "count" in a diet are kcal's)
Importantly, it takes about 540 calories to turn 1 ml of water to vapor.
Thus, for evaporation, we lose a lot of heat by panting or sweating.
This is called "insensible" water loss, not because it does not make sense but because you are not aware of it as you are for micturation.
Ectotherms "cold" (ambient) blooded.
Endotherms (homeotherms).

Figs. 1.3 and 1.4
"set point" 37oC
Humans - 98.6oF = 37oC
Reset thermostat's set point in fever (pyrogens).
Antipyretics (like aspirin) or hibernation lower set point.
Produce heat by shivering or increasing metabolism (with thyroxine, epinephrine)
Decrease heat loss: Arrector pili (smooth muscle) for piloerection (fluffing fur) , vasoconstriction (closing peripheral capillary beds).
Increase heat loss by panting [for dog] or sweating [for person] or vasodialtion.

Homeostasis: weight regulation

One of my favorite examples of regulation is weight regulation. My fellow graduate students and their professor in the early 1970's studied the hypothalamus, a part of the brain you will see in a few minutes, and its involvement in weight regulation. People actually regulate their food intake well. It is stated that no calories are lost (in feces or urine) [except that glucose is lost in urine of people with untreated diabetes]. Thus, you eat the same amount you need for energy catabolism (2000-3000/day) or else you gain or lose weight. I checked the calculations and found that 250 extra calories per day (1 cookie/day) would result in gaining 25 lb/yr (and very few people are gaining or losing weight that precipitously).

Levels of analysis

Levels of analysis (from introductory biology):
element - molecule - organelle - cell - tissue - organ - organ system - organism - population - biosphere

Levels of analysis (for this human physiology course):
cell - tissue - organ - organ system - organism

Integrating body functions

To make everything function in cooperation, systems of integration are needed:
(1) hormones (examples of homeostasis, next)
(2) nervous system (first major topic of the semester)

Fig. 6.29
shows these mechanism as well as paracrine (local hormone)
In both cases, a chemical is used.
Neuron uses small amount of neurotransmitter applied directly to target (muscle, nerve or gland)
Endocrine (ductless) gland (as opposed to exocrine gland with duct) puts a larger amount of hormone into blood stream where it can affect one or several target organs.

Homeostasis - hormones

TRANSPARENCY (review figure from introductory biology)
Here's the bottom middle of the brain, the hypothalamus.
Also, the pituitary to which the hypothalamus connects.
The anterior part of the pituitary puts out ACTH (adreno cortico tropic hormone).
["AC" refers to adrenal cortex, "T "refers to trophic effect, "H" stands for hormone.]
ACTH positively regulates the cortex of the adrenal gland (just north of the kidney).
The adrenal cortex puts out cortisol that feeds back negatively the anterior pituitary to decrease ACTH.
The Hypothalamus sends CRF (corticotrophin releasing factor) through the portal vessel to the anterior pituitary for ACTH release.
[Explanation of "portal" -- Mostly, the circulatory system is "wired" in "parallel," but for 3 systems, hypothalamus->pituitary, intestine->liver and kidney cortex->kidney medulla, the blood flows first to one then to the other, i.e. it is "wired" in "series".]
ACTH feeds back negatively to the hypothalamus to decrease CRF.

Fig. 11.16
[a similar example from your text]
TRH (thyrotropin-releasing hormone) (Note, "hormone" term, "factor" above.)
TSH (thyroid stimulating hormone)

Fig. 11.3
"Thyroxine" has two forms, T3, T4, formed from dimer of tyrosine (amino acid) with 3 or 4 iodines attached.

What everybody should know about thyroid hormone:

Fig. 11.25
Goiter insufficient dietary iodine

Fig. 11.24 TRANSPARENCY
Goiter

Figure 11.26 TRANSPARENCY
Hyperthyroid syndrome in adult

TRANSPARENCY
Cretinism hypothyroid in infant

Dietary iodine is from sea food. Now iodine is added to salt.
It is because of thyroxine that you should worry if there is a reactor leak (like 3 mile Island or Chernobyl), and the solution is taking lots of iodine so that any radioactive iodine you are exposed to will be competitively swamped out for thyroid uptake.

Roger Guillemin and Andrew V. Schally won the 1977 Nobel Prize for their discovery of these releasing hormones (factors), a heroc task because they are present in vanishingly small amounts (because of the efficiency of hormone delivery through the portal vessel).

References
(1) see p. 117, G. Audesirk & T. Audesirk, BIOLOGY Life on Earth (3rd ed.), New York, Macmillan, 1993.
(2) see pp. 48-49, D. J. Aidley, The physiology of excitable cells, Cambridge, University Press, 1971.
(3) see pp. 34-35, B. Katz, Nerve, muscle and synapse, New York, McGraw-Hill, 1966
(4) S. Freeman, Biological Science, Upper Saddle River, NJ, Prentice-Hall, 2002

Exam questions from 2004 - 2008 relevant to this lecture

Under what circumstances does a person lose calories via the urine?

untreated diabetes

What is an anabolic steroid?

a hormone like testosterone that bromotes muscle growth

Why might you take iodine supplements if you are downwind of a reactor accident?

have more "cold" iodine to compete with radioactive iodine for T3 and T4 incorporation

"Tropic," the "T" in "ACTH" means affecting the activity of. Specifically, on what gland does ACTH have this trophic affect? (i.e. What does the AC stand for?)

adrenal cortex

What does piloerection do to regulate back to the set point?

fluffing the fur prevents heat loss

Name a substance for which the portal vessel from the hypothalamus to the pituitary is specifically "designed."

TSH, others like it

What does panting achieve for a dog?

evaporative cooling

ACTH triggers the release of what hormone from its target gland?

cortisol

Relate the statement "Aspirin is an antipyretic" to the concept of homeostasis.

pyrogens reset the thermostat to cause fever

"Insensible" is a term applied to water loss by perspiration or panting in contrast with the water loss by micturition. What does "insensible" mean?

you're not aware of it

Relate the amount of energy an average adult uses per day in catabolic metabolism to the energy needed to increase the temperature of 1 ml of water by 1 degree C.

2000 k cal / day relative to the definition of one calorie

What is the set point for the human hypothalamic thermostat in degrees C?

37

Why are sweating and panting so effective for increasing heat loss?

the heat of vaporization is 540 cal

Why is the term "anabolic" applied to steroids abused by some athletes?

they cause build-up as oppoaed to break-down (in catabolism), in this case of muscle mass

How does aspirin affect the set point of the thermostat?

it is antipyretic

What would be specified with the term "catabolism" in distinction with the more general term "metabolism?"

breakdown

How does vasoconstriction decrease heat loss?

Less radiation of warmth from extremeties

Why is testosterone referred to as an "anabolic steroid?"

it favors muscle growth

If there were a deficiency of iodine in the diet, which pituitary hormone would be produced in excess, leading to goiter?

TSH

ACTH has a negative feedback to control what hypothalamic hormone in order to regulate its own (ACTH's) level?

ACTH

Why is it especially useful for a person to sweat when hot?

Evaporative heat loss

In terms of the human thermostat, when would shivering be a useful behavior?

Muscle activity generates heat

"You do not lose calories through your feces and urine." What is the most notable exception to this generalization?

Untreated diabetes mellitus

Why don't most people gain or lose a lot of weight rapidly?

homeostasis - they eat the right amount

State one of the physiological mechanisms for decreasing heat loss in mammals.

piloerection, vasoconstriction

Why are some steroids are called "anabolic?"

they favor growth

"Neurotransmitters are strategic because they are so discrete and thus use a minimum amount." Why on earth would there be hormones then?

they reach many areas

How does glucose get into the cell?

transport, facilitated and co-transport with sodium

What hormone does the adrenal release in response to ACTH?

cortisol

There is a lot less TRH than TSH. Why?

TRH delivered neatly via portal system

How is paracrine signaling distinguished from endocrine signaling?

paracrine is local

Why is panting and perspiring so effective to increase heat loss?

because of the large heat of vaporization of water

A fat is a triglyceride. How come membrane lipids have only two fatty acids in text book diagrams? (i.e. What is the third item linked to the glycerol?)

the polar head group

"Endemic" was the term your text used for (what?) disorder of inland people who had no seafood (in the old days)?

goiter

The lay expression for ectotherm is "cold-blooded." Why is that inaccurate?

More like they assume ambient temperature

How come homeotherms (endotherms) always have heat available for maintaining body temperature at the set point?

Because of inefficiency in metabolism, waste is heat

In addition to triiodothyroxine, what is the other thyroid hormone?

T4

In your homeostasis lecture, ACTH was used as an example. What keeps ACTH levels from getting real high?

homeostasis (negative feedback from cortisol)

Adrenalin comes from the adrenal medulla. By contrast, where does ACTH exert its trophic effect?

adrenal cortex

What is the opposite of vasodilation and what is this (the opposite of vasodilation) useful for (in terms of homeostasis)?

vasoconstriction would decrease heat loss (body's thermostat)

A diagram from the introductory biology book showed how hypothalamic CRF (corticotropin releasing factor) caused the anterior pituitary to secrete ACTH (adrenocorticotropic hormone). Why is this hormone referred to as CRF?

corticotropin = ACTH, factor=hormone, causes its release

Guillemin and Schally won a Nobel Prize for for their discovery of releasing hormones (factors), a heroic task because they are present in vanishingly small amounts. Why can there be such small amounts of these hormones (compared with other hormones).

portal vessel delivers it without dilution

A nuclear reactor spews out radioactivity upwind of where you live. Quick! What should you eat to minimize thyroid damage?

nonradioactive iodine to compete with the radioactive for uptake


this page was last revised 6/10/09

**The Membrane Lecture

Membranes

Fox, Chapter 6, plus some references back to earlier and later chapters and to Freeman

There's enough lipid to make two layers

Fig. 6.13
shows how red blood cells react to hypertonic, isotonic and hypotonic solutions.
Get a good source of membranes:
red blood cells (erythrocytes) from adult human have only plasmalemma.
Gorter and Grendel showed in1925 that there was enough lipid to make two layers.
Put red blood cells into distilled water, they burst from hyposmotic shock and become only "ghosts" - membrane only.
Blood cell counts, and geometry solves for membrane surface.
Extracted lipids on a surface have an increased lateral stability when they reach a monolayer which, when measured is twice the membrane area.
Here is a snapshot I took of oil on a road after rain - when oil is multiple layers, you see color, and layers slip, when oil is one layer, it is black.

Fig. 6.7
(To understand how hypotonic shock burst the erythrocyte, I introduce a fundamental concept, osmosis)
Osmosis - water moves passively from where water is at a higher concentration (for instance pure water) to where water is at a lower concentration (where organic chemicals are dissolved in it)
through a semipermeable membrane (i.e. a membrane which passes water but not the organic molecules).

Membrane structure

TRANSPARENCY (Review from an introductory text)
glucose transporter, like

Fig 6.16
shows bilayer of lipids with protein in it

Notice that the lipid molecules are drawn in this "cartoon" as a ball with two sticks.
Most membrane lipids are phospholipids with:
(1) a polar (hydrophilic) head group
and
(2) hydrophobic fatty acid (acyl) tails

Another example allows introduction of another fundamental molecule:

TRANSPARENCY (Review from an introductory text)
Here is a famous membrane protein, rhodopsin, the molecule we see with, and how 7 hydrophobic alpha helices of the protein fit into the hydrophobic part of the membrane (the milieu created by the fatty acid tails). For future reference, retinal is the chromophore, the component (chromophore) that makes the protein [proteins are otherwise not colored] into a pigment. Retinal is a derivative of vitamin A. Rhodopsin is in the membranes of rods and cones, visual receptor cells, shown in the diagram. Rhodopsin is the prototypical G protein-coupled receptor (GPCR), and GPCRs are used for hormones, neurotransmitterss, olfaction, taste and others.

Electron microscopy (EM)

Fig. 3.2, Fox
Robertson did work that led to earlier bilayer model.
He saw 2 "electron dense" (dark) lines in EM when stained osmium, an electron dense heavy metal. Davson and Danielli developed a membrane model from Robertson's vistas.
Fluid mosaic Singer and Nicolson the more modern version

Picture I made freeze fracture replicas with this apparatus. Specimen is prepared, frozen to liquid nitrogen temperature, put inside a vacuum, smashed with a razor (membranes break down the middle between the fatty acid tails), blasted from an angle with a platinum gun (to shadow protein with electron dense heavy metal), blasted from above with a carbon gun (to hold replica together), then the tissue is dissolved away.

Here, from my research, is an example of how things look. Picture shows visual membranes in Drosophila. High vitamin A flies have membranes full of protein (the same rhodopsin I mentioned above) while vitamin A deprivation decreases this protein.

Membrane biochemistry

Membrane lipids are composed of:
(1) Phospholipids such as phosphatidylcholine (lecithin)
I did some research on the phospholipids of the Drosophila head. Using radioactively lbeled phosphate, many different phospholipids are visualized after they have been separated on a TLC (thin layer chromatography) plate.
(2) Cholesterol
(3) Glycolipids such as one that accumulates in Tay-Sachs, a hereditary lysosomal storage disease,1/30 American Jews carry, recessive, fatal at 6 mo - 5 yr

Alexa B. Serfis in SLU's Chemistry Department studies membrane lipids and their proteins

Membrane physiology

Relevant to physiology, if the membrane had only lipids, it would have extremely high resistance. This is because the hydrophobic milieu in the center of the membrane does not allow water, a polar solvent, or ions which carry current. The membrane is only permeable because some of the proteins are channels that pass ions. Also, there is high capacitance. The concepts of resistance and capacitance will be dealt with shortly.

Membrane signalling

Lipid makes a barrier to anything polar or big like protein hormone or epinephrine (bind receptor).
(This receptor is the GPCR, mentioned above.)
Steroid hormones can go in

It used to be thought that lipids just sit there. In the 1980's it became clear that they turn over metabolically and that some products of membrane lipid turnover are important mediators of intracellular signalling. This is very fundamental and will come up repeatedly in later.

Fig. 11.9, Fox
Hormone -> receptor protein (GPCR) -> G-protein -> cascade makes second messengers (IP3 and DAG [diacyl glycerol, not in your diagram]) from the membrane lipid PIP2 [phosphatidylinositol-4,5-bisphosphate, not in your diagram], note that calcium ion Ca2+) becomes a next messenger in the cascade.

Important points that will come up repeatedly:
Phospholipase C is the enzyme [and I have a research interest in PLC]
IP3 is a "ligand" for a calcium channel.
Ca2+ is sequestered inside endoplasmic reticulum.
Inside a cell's cisterns is tantamount to outside the cell.
Ca2+ is high outside and low inside, like Na+ (sodium ion) unless deliberateluy increased intracellularly.
Ca2+ levels are so important that 3 hormones regulate blood Ca2+, parathormone, calcitonin and vitamin D.

Membrnne channels

Fig. 7.26
Nicotinic Acetylcholine receptor [More on this later])
Acetylcholine is a ligand (neurotransmitter), nicotine is a pharmnacological agonist.
This receptor is a channel (for ions, giving the membrane electrical conductance [g])
Channel is ligand gated.
Sodium (Na+) and potassium (K+) shown going through pore in membrane that can be open or closed.
Sodium, higher outside the cell, is likely to go in.
Potassium, high inside the cell is likely to go out.

The 1991 Nobel prize in physiology and medicine was awarded to prize was awarded jointly to: ERWIN NEHER and BERT SAKMANN; they developed patch clamping that allowed electrical recording from single channels.
In 1963 the Nobel prize was awarded jointly to: SIR JOHN CAREW ECCLES , SIR ALAN LLOYD HODGKIN and SIR ANDREW FIELDING HUXLEY for their discoveries concerning the ionic mechanisms involved in excitation and inhibition in the peripheral and central portions of the nerve cell membrane; Hodgkin and Huxley worked on the voltage gated channels of the axon's action potential and Eccles worked on the neurotransmitter gated channels at synapses.
In summary, the topic of ion channels is pretty fundamental.

Fig. 7.21
Also holes in membranes from one cell to another are important:
Gap junctions - 2 hexamers in register of connexin protein
This is a very big channel.
Important in many places, especially connecting one heart muscle (myocardial) cell to another electrically.

Membrane transport

Fig. 6.19
"sodium pump"
A large fraction of the cell's energy (ATP) goes to pumping ions (active transport)
This creates an ion imbalance, sodium Na+ high outside cell, potassium K+ high inside.
This gives rise to the membrane electrical potential (voltage) important in nerve and muscle cells.

Fig. 3.4
bulk transport:
phagocytosis - cell eating
pinocytosis - cell drinking
Receptor mediated endocytosis - clathrin coated pits turn to vesicles, clathrin is a protein that makes vesicles look fuzzy.
Receptor mediated endocytosis is important in clearing lipoproteins, LDL and HDL, from blood (later), and, of course, a receptor protein in the membrane is important in the transport.
From my research, a coated pit.

In summary,

Functions of membrane proteins
(1) transport
(2) many enzymes are on the membrane
(3) receptors for hormones, neurotransmitters and developmental signals are on the membrane.
(4) cells are joined by proteins
(5) cells communicate by proteins
(6) cells hook to extracellular proteins by proteins

Reference:

E. Gorter and F. Grendel, On bimolecular layers of lipoids on the chromocytes of the blood, J. Exp. Med. 41, 439-443, 1925

Exam questions from 2004 - 2008 relevant to this outline

With answers

Why do you need lead, osmium, uranium or platinum to see aspects of membrane structure in the electron microscope?

heavy metals are electron dense

What did hypotonic shock do to what kind of cells to allow Gorter and Grendel to show that there was enough lipid in the membrane to make two layers?

burst red blood cells to make red blood cell ghosts with a measured membrane surface area

Why do you need a chromophore (such as retinal for rhodopsin and heme for hemoglobin) to make a protein into a pigment?

proteins do not absorb visible light

How does a steroid hormone get into a cell?

that can pass the lipid barrier

How do sodium ions get forced out of the cell?

active transport with a protein that uses ATP

The nicotinic receptor is a cation channel for what two ions?

K+ and Na+

Rhodopsin and neurotransmitter and hormone receptors interact with what downstrean heterotrimeric protein?

the G protein

What do you call electrical junctions from cell to cell with channels composed of hexamers of connexin protein in register?

gap junctions

What must be bound to the G-protein-coupled-receptor protein to make the fully-functional rhodopsin molecule that absorbs light?

retinal

As a result of phospholipase C (PLC) activation, what ion is released into the cytoplasm from smooth endoplasmic reticulum?

Ca2+

In what fundamental way does the location of a steroid hormone receptor differ from that of the receptor for epinephrine?

steroid receptor is in cell, epinephrine receptor is in membrane

In a "cartoon" of a membrane phospholipid, there is a ball with two tails. The ball is the polar (hydrophilic) head group. What are the two tails?

fatty acids (acyl groups)

Which direction does the ATPase pump sodium ions?

out of the cell

Epinephrine binds one G protein-coupled receptor (GPCR). What other GPCR, used for vision, is a pigment that contains a form of vitamin A?

rhodopsin

What is the name of the electrical connection between myocardial cells composed of connexin proteins?

gap junction

Why does an erythrocyte turn into an erythrocyte ghost when placed into distilled water?

because of osmosis, it swells and bursts

When a membrane lipid is drawn as a ball with two sticks in a diagram, what are the ball and sticks respectively?

polar head group, fatty acids

One signal transduction product of phospholipase C (PLC), diacylglycerol (DAG), is in the membrane while the other, IP3, inositol trisphosphate, goes into the cytoplasm. Where is the precursor, PIP2 (phosphatidylinositol-4,5-bisphosphate)?

it is a membrane phospholipid

When the nicotinic acetylcholine receptor channel opens, there is an efflux of K+. Why?

because it allows Na+ and K+, so K+ goes down its chemical gradient

One membrane protein is sometimes called the Na+-K+-ATPase. What is its function?

pumps Na+ out, K+ in

What is the function of a hexamer of connexin proteins in one cell's membrane in register with a similar hexamer on the adjacent cell?

gap junction connects adjacent cells' cytoplasm and passes current

How can it be that a cortisol receptor is intracellular while so many hormone receptors, for instance for epinephrine, are on the membrane?

steroids pass through the membrane

Robertson's pioneering electron microscopy paved the way for Davson and Danielli's bilayer membrane model and Sanger and Nicolson's fluid mosaic model. Why were heavy metals like osmium necessary for that demonstration?

Electron dense

If water and ions are excluded from the center of the membrane, where fatty acids reside, how is it that a G protein-coupled receptor can span the membrane?

There are hydrophobic amino acids

Tay-Sachs disease is a fatal autosomal lysosomal storage disease. What accumulates?

glycolipid

Before I introduced metabotropic receptors (G protein coupled proteins that bind a ligand such as a neurotransmitter), I showed rhodopsin, the prototypical G protein coupled receptor. Why doesn't rhodopsin need to have a ligand bind to it? (i.e. What does it have that a neurotransmitter receptor does not have?)

it has retinal, a vitamin A derivative

Researchers have been able to make artificial membranes out of phospholipids in a hole between two compartments in a water bath. Why would membrane lipids naturally arrange themselves as they are aligned in membranes?

polar heads would orient to water and hydrophobic tails toward eachother

In the phosphoinositide signal cascade, phospholipase C (PLC) makes "second messengers" IP3 (inositol trisphosphate, the polar head group) and what(?) from the membrane lipid PIP2 (phosphatidylinositol-4,5-bisphosphate.) [If you do not remember, I have put enough information into the question that you should be able to figure it out.]

diacyl glycerol

Osmosis was referred to as passive transport. Is the sodium-potassium pump passive? Justify.

no, it is active b/c it uses ATP

After feeding radioactive phosphate, extracted lipids were visualized by audioradiography of a TLC (thin layer chromatography) plate. Why didn't I see the sort of lipids that accumulate in Tay Sachs disease?

it is glycolipids and would not take up phosphate

If you fracture a frozen membrane, proteins are exposed. But you cannot see them in the transmission electron microscope unless you do something. What?

you need to make a replica, shadow it from an angle with an electron dense material (platinum)

Under what circumstances (what do you do?) does a passive process (what process?) let you make a red blood cell ghost from a red blood cell?

Put r.b.c into distilled water, osmosis

Tell me about a famous lysosomal storage disease. Your answer can be biochemical, cell biological, or genetic.

Tay Sachs fails to break down a glycolipid that accumulates in the cell, autosomal recessive carried in Ashkenaze Jews

In the transmission electron microscope, what membrane specialization of receptor mediated endocytosis is visualized?

Clathrin coated pits (vesicles)


This page was last updated 6/15/09

**The bioelectric potential lecture

Neurons

Fox Chapter 6 and 7. Note that web material is especially important for this lecture

Figure 7.1a
typical neuron
Connections, from other neurons, created graded electrical potentials at synapses, on dendrites and cell bodies.
Cell body integrates the synaptic excitatory and inhibitory voltages.
If there is net excitation, axon propagates the all-or-none, non -decemental action potential quickly over long distances.

Overview

Excitable membrane has resting and action potentials
Ions are dissolved in water and are pumped using ATP -> ADP for energy, Na+-K+-ATPase.
This "sodium pump" uses 1/3 (2/3 if high electrical activity) of cell
These ion gradients establish "batteries" as ions can flow through channels.
Other than channels and pumps, membranes do not pass ions well (covered before).
For resting potential, Potassium (K+) channels dominate.
For action potential, Sodium (Na+) channels open (activate) then close (inactivate).
Toward the end, a different type of K+ channels open (activate) then close (passively, they do not inactivate).
Action potentials are all-or-none big depolarizations.
Synaptic (graded) and sensory (generator) potentials are smaller.
They can be of variable size and can be depolarizing or hyperpolarizing.

History

1791 Luigi Galvani (Italy) (of Galvanometer fame) - nerve muscle electricity in frog
1850 Herman von Helmholtz - speed of conduction (40 m/s)

Walther Hermann Nernst (Germany) (1864-1941) 1920 Nobel in Chemistry.
Nernst equation says that ion gradient is equal and opposite to voltage difference.
(often misunderstood)
1902 (paper) Julius Bernstein apply Nernst, K+ permeability lost in action potential.
(insightful but short of the full story)

TRANSPARENCY (from R. D. Keynes, The nerve impulse and the squid, Scientific American, December, 1958).
squid giant axons
1939 K. C. Cole and H. J. Curtis (US) introduced use of squid and showed that membrane resistance decreases during passage of action potential
Invertebrates do not have myelin to speed the velocity of propagation of the action potential.
Theoretically, this velocity increases with the radius, and so invertebrates use giant axons when fast action potentials are needed.
Squid uses quick mantle contraction and jet propulsion through siphon in escape response.

1950's Sir Alan L. Hodgkin & Sir Andrew F. Huxley (Great Britain)
1963 Nobel Prize in Physiology and medicine for "ionic mechanisms...excitation inhibition...nerve cell membrane"
In general, They showed what was stated above:
For action potential, Na+ channels open then close, K+ channels open (then close)

Electrical concepts

Fig. 6.26, Fox
Sodium is high outside.
Potassium is high intracellularly.

pdf
Circuits (equivalent circuits)
Battery, anode:+, anions:-, Cathode:-, cations:+
Current = i (Amps), defined as + to - (Benjamin Franklin)
Potential (potential difference): V or E (Volts)
(1) Battery (source of electromotive force, EMF)
(2) Current flow through a resistor
battery and resistor in circuit
E = IR (Ohm's law), R in units of Ohms, W
G is conductance, 1/R, "mho" = Siemens (S)
I = gV

delay in depolarizing or hyperpolarizing membrane
Membrane capacitance
Thus, this is a low (frequency) pass (high cut-off) filter
Typically, capacitance adds delays
There are also high pass filters

Derivation of Nernst potential

Fig. 6.26, Fox (again)
Because of the potassium gradient there is a resting potential of about -65-70 mV

pdf
Assume two compartments in communication
(ions like K+ or Na+ dissolved in each)
Free energy (of each system) = RT ln Ci + ziFF
chemical electrical
F is absolute potential, C is concentration, i is given ion, e.g. K+ or Na+
T is tempreature in degrees Kelvin
R = 8.31 Joules/moleoK
F = 9.65 x 104 Coulombs/mole
[ = 6.02 x 1023 ions/mole x 1.6 x 10-19 Coulombs/ion ]
Assume equilibrium which means
(1) no flux
(2) electrical and chemical gradients equal and opposite
(3) energies of two compartments the same
Simple algebra and the fact that log10 = 2.3 x ln gives:
EK+ = 58 log [K+]out / [K+]in

K+ in 140, K+ out 5
Na+ in 5-15, Na+ out 145

Fig. 6.27
Because of the potassium gradient there is a resting potential of about -65-70 mV
(like before but with voltmeter drawn in

Goldman equation

pdf

There is an equation that looks like the Nernst equation except that is has sodium (Na+), potassium (K+) and chloride (Cl-) and their relative permeabilities. Permeabilities change as a function of time.

David Goldman, 1943
assume constant field, this derivation is "beyond the scope of this course" (way too dificult)

Vm = 58 log PK[K+]out + PNa[Na+]out + PCl[Cl-]in
PK[K+]in + PNa[Na+]in + PCl[Cl-]out

(see pdf for equation drawn more neatly)

Note that in and out are reversed for Cl- since it is an anion while Na+ and K+ are cations.

There is a membrane model with 3 batteries (note that the sodium and potassium batteries are reversed because the gradients of these two cations are opposite).

The relative permeabilities are modelled by variable resistors (potentiometers) [where variable conductances, the inverse of resistances, are more analogous to variable permeabilities]

Wheatstone bridge

How to determine an unknown resistor
Use two knowns as voltage divider
use a variable and the unknown as another voltage divider
Use a galvanometer as a null detector between the two nodes

Cole and Curtis used an AC bridge to show that resistance decreased during the action potential

Kirchoff's laws

Such a membrane model seems to suggest a confusing circuitry, simplified by several simple concepts.

Kirchoff's first law: at any junction, sum of currents is zero.

Kirchoff's second law: sum of changes in potential around loop is zero.

There is a pdf to illustrate a problem and its solution using Kirchoff's laws.

The solution involves 3 equations with 3 unknowns (high school algebra)
[or determinants, slightly more advanced high school algebra].

Reference

R. D. Keynes, The nerve impulse and the squid, Scientific American, December, 1958

Exam questions from 2004 - 2008 relating to this outline

Write an equation obeying Ohm's law relating voltage and current but using conductance rather than resistance.

if E=IR (Ohm's law), then E=(1/g)I, so I=GE

What is assumed in the derivation of the Nernst equation?

energy of two compartments is the same which is tantamount to saying that electrical and chemical gradients are equal but opposite

What two components are used in the circuits of high- and low-pass filters to give them the property of having a time constant?

R & C

Permeability to what ion increases at the beginning of the action potential?

sodium

Write an equation expressing conductance as a function of resistance.

G=1/R

Faraday's constant (9.65 x 104 Coulombs/mole) is important in expressing electrical component of energy of a thermodynamic system. What do you need to multiply the charge of an individual ion (1.6 x 10-19 Coulombs/ion) by to get Faraday's constant?

Avagadro's number (the number of ions per mole)

What is the name and polarity of the electrode to which cations would migrate in solution?

cathode is negative

After the nerve cell integrates the excitatory and inhibitory post-synaptic potentials, which part of the cell propagates the action potential (if threshold is reached)?

axon

If I graphed Ohm's law with Voltage on the Y axis and current on the X axis, I would get a line. What is the slope?

R

Invertebrates do not have myelin. What adaptation allows for fast action potentials in invertebrates?

giant axons

What type of impedance makes it so that Voltage would change as a function of time?

capicitance

What is the expression commonly used to describe an action potential and to differentiate it from a graded synaptic potential?

all-or-none

What is the term for the inverse of resistance, an electrical term analogous to relative permeability?

conductance, g

There are two components of energy in a thermodynamic system. Which component is RT times the log of the concentration?

chemical energy

Both resistance and capacitance are membrane impedances. In what way is capacitance distinguished from resistance?

Voltage across capacitor changes as a function of time

The squid does not have myelin. How does the squid have fast action potentials?

Giant axons

Around 1900, Bernstein explained the action potential by a loss of the selective K+ permeability during the action potential. Although insightful, this was two bricks shy of a load. What, in fact, changes and in what direction.

Na+ permeability goes up (depending on how you read "what direction," inward flow)

Voltage can arise from a battery and (what else)?

current flowing through a resistor

How does the capacitance of the axon compare with that of the axon membrane plus the myelin?

many membrane layers, each with capacitance, add reciprocally, hence the answer is "lower with myelin"

People do not have giant axons while squids do. How do we achieve, in our axons, what squids do with that adaptation (giant axons)?

myelin

What happened to axon resistance when Cole and Curtis used the AC Wheatstone bridge as the action potential was passing?

went down

When batteries and resistances for sodium and potassium are drawn to model the Goldman equation, what special properties do the resistors have to account for the resting and action potentials?

must be variable (potentiometers)

How do Schwann cells vs oligodendrocytes differ with respect to investing axons with myelin?

Schwann, one axon, oligo a few

During propagation of the action potential, what depolarized the axon to threshold at any given location?

the action potential at one place triggers

A deliberate slight of hand had me graphing Ohm's law with the X and Y axes reversed. Thus, we talked about "conductance" which relates to what way of describing how well ions traverse a membrane channel?

permeability

Why might a middle-aged person who had recovered partially from "infantile paralysis" (polio) experience a relapse?

Post polio syndrome has sprouts of motor neurons going away (motor unit goes back to before recovery of function)

In terms of understanding resting, graded and action potentials, what does the Goldman equation (and its equivalent circuit) convey that the Nernst equation does not?

it takes into account several ions and their relative permeabilities

Applying the equilibrium assumption in deriving the Nernst equqtion (both thermodynamic systems have the same energy) we show that the electrical potential difference (across the membrane) is equal and opposite to (what?)?

chemical gradient

A current is injected into a membrane to change the membrane's voltage. How does the membrane capacitance change the membrane voltage?

it causes delay (as the membrane capacitance charges)

A deliberate slight of hand had me graphing Ohm's law with the X and Y axes reversed. In this "I-V curve" what is the slope of this line?

conductance (g)

Why do squids have giant axons? Your answer can be behavioral, it can pertain to the properties of giant axons, or it can be comparative (comparing squid with "higher" nervous systems).

so they can contract their mantle for the escape response synchronously, giant axons conduct faster, invertebrates do not have myelin

Why is salutatory conduction so much faster than conduction without myelin?

all that insulation forces the action potential to jump way ahead to the next node of Ranvier

Why is the prefix "oligo" applicable to olidodendrocytes?

they myelinate several axons in the CNS

"Capacitors in series add reciprocally." What does this say about the capacitance of myelin?

less current would leak out of the axon through the membrane capacitance where there is myelin

Why do squids have giant axons? Your answer can be behavioral, it can pertain to the properties of giant axons, or it can be comparative (comparing squid with "higher" nervous systems).

so they can contract their mantle for the escape response synchronously, giant axons conduct faster, invertebrates do not have myelin

Why is salutatory conduction so much faster than conduction without myelin?

all that insulation forces the action potential to jump way ahead to the next node of Ranvier

Why is the prefix "oligo" applicable to olidodendrocytes?

they myelinate several axons in the CNS

"Capacitors in series add reciprocally." What does this say about the capacitance of myelin?

less current would leak out of the axon through the membrane capacitance where there is myelin

By passive spread, a spike at one place depolarizes the axon ahead of it (and behind it) to threshold. Why is conduction unidirectional?

because the sodium channels behind it are inactivated, causing the absolute refractory period

Why might a middle-aged person who had recovered partially from "infantile paralysis" (polio) experience a relapse?

Post polio syndrome has sprouts of motor neurons going away (motor unit goes back to before recovery of function)

An oscilloscope presents the action potential like a graph. What are on the X and Y axes?

X time, Y voltage

Why was Golgi's technique, so exquisitely used by Ramon y Cajal, a contribution worthy of the Nobel Prize?

Among a zillion cells, one cell could be seen in its entirety



This page was last updated on June 16, 2009

**The action potential lecture

Action Potentials

Fox, Chapter 7 (mostly)

Spike propagates nondecrimentally long distances

Fig 7.4
Typical nerve
Most important information - axon is relatively long.
There are various shapes.
Top - this looks likes the input to the spinal, the cell is in the dorsal root ganglion
Middle - there are bipolar neurons in the retina
Bottom - this looks like the spinal motor neuron, cell in ventral horn of spinal cord gray matter.
In this multipolar neuron, synapses are on dendrites and cell body, axon carries action potential

Fig. 7.11
oscilloscope essentially graphs voltage as a function of time
The figure introduces the terms depolarization and hyperpolarization

Properties of the action potential

Fig. 7.13
(What everybody should remember about the action potential based on the background you are assumed to have.)
At threshold, Na+ channels open (then close), and Na+ diffuses in
After peak of action potential (spike), K+ channels open, and K+ diffuses out
The spike is all-or-none, as opposed to having variable sizes like synaptic potentials or receptor potentials.
After the spike, there is a refractory period (when another spike cannot be started), and this insures unidirectional propagation.
Note that the depolarization to threshold shows the membrane acting as a low pass filter.

Fig. 7.19
Spike depolarises the axon ahead of it to depolarize the membrane to threshold

Passive propagation

Introduction. "Action" potential refers to the active voltage-gating that opens the Na+ channel that allows nondecremental propagation. If that did not happen, propagation would be decremental based on the passive spread of current going down the axon and also leaking out the membrane.

Fig. 7.19
(look back, I already showed it)
Current going down axoplasm and leaking out membrane
The recorded potential gets smaller

pdf
Cable equation

Summary:
(1) an action potential at one place depolarizes the membrane ahead of it to threshold.
(2) the spread is passive.
(3) current down the axoplasm leaks out through membrane resistance and capacitance.
(4) solving, space constant varies with square root of radius, time constant independent of radius.
(5) that is why invertebrates use giant axons for fast propagation.

Myelin speeds up the action potential

Fig. 7.7
Transmission electron micrograph (TEM) of myelin.
Membrane is wrapped around and cytoplasm is squeezed out, leaving only alternating bands of electron density and lucency at high magnification.
Each layer of membrane has high resistance, and resistors in series block current flow through membrane.
Each layer of membrae has high capacitance which would leak current, but capacitors in series add reciprocally, decreasing capacitance and leakage.

Fig. 7.20
Myelinated axons have faster propagation.
Invertebrates do not have myelin, and that is why they have giant axons.
Here's why: action potential jumps from one node of Ranvier to next, "saltatory" (leaping) conduction

Myelin is invested by different cells in peripheral vs central nervous systems

Fig. 7.6
In PNS (peripheral nervous system), myelin is made from multiple membrane wrappings of Schwann cell.
One axon
Disrupted in polio (poliomyelitis)

Polio (poliomyelitis) is a viral disease that damages myelin in peripheral nervous system causing paralysis; then the nerve cell degenerates.
Salk (1955, injected) then Sabin (eat sugar cube) vaccines in the 1950s, before that, only passive immunity from gamma globulin from people who had polio.
Serious cases required an iron lung.
FDR had polio.
Neuron's trophic effect on muscle is seen as muscle (not directly diseased) deteriorates.

Recent literature
It is thought that there is some recovery where motor neurons branch more (they already branch to innervate all of the muscle cells [fibers] of one motor unit) so that surviving neurons
innervate muscle cells "abandoned" by lost nerve cells.
But at middle age, there is increased fatigue, pain and weakness (post-polio syndrome).
Cause: those sprouts are lost.
L.S. Halstead Post -polio syndrome, Scientific American, April 1998 42-47

Fig. 7.8
In CNS (central nervous system), myelin is formed from oligodendrocytes.
Multiple axons, hence the prefix "oligo" (a few).
Disrupted in multiple sclerosis.

Multiple sclerosis (MS) (Anette Funicello, Montell Williams, Richard Prior, "the president" in West Wing) damages myelin in the central nervous system
Might aflict motor function, vision, or others
Hits people 20-40, with deterioration but sometimes episodic, i.e. with remissions
Animal model - EAE (experimental allergic [autoimmune] encephalitis) to myelin basic protein.
Such a disorder used to happen with rabies vaccination when virus was gron in brain (before it was grown in eggs).

Hodgkin Huxley Nobel experiments

Fig. 7.14
resting potential is based on predominant K+ permeability
then Na+ channels activate
then Na+ channels inactivate
then a late K+ channel activates

Channels

GENERALIZATION - action potential is based on Na+ and K+
there are MANY other channel types

Fig. 7.12
inactivation is "stopper" on chain

Tetrodotoxin puffer fish (saxitoxin dinoflagellates) block Na+ channel

Questions from 2004 - 2008 that relate to this outline

You apply a depolarization (below threshold for triggering an action potential) at a certain place along the axon. Why would it get smaller the further away from this place that you
record?

because current leaks out through the membrane

What is a disease of central nervous system myelin?

multiple sclerosis

What electrical properties of myelin contribute to saltatory conduction?

R & C

Permeability to what ion increases at the beginning of the action potential?

sodium

According to cable equation calculations, how does the speed of propagation relate to the radius of the axon?

square root of radius

Describe a difference between an oligodendrocyte and a Schwann cell.

myelinate several vs one axon, also CNS vs PNS

After the nerve cell integrates the excitatory and inhibitory post-synaptic potentials, which part of the cell propagates the action potential (if threshold is reached)?

axon

Invertebrates do not have myelin. What adaptation allows for fast action potentials in invertebrates?

giant axons

If current from a depolarizing stimulus travels down the axoplasm, how come the recorded voltage would get smaller with increasing distance from the stimulus (according to the passive, "cable" properties)?

because current leaks out through membrane resistance and capacitance

What property keeps the action potential from triggering an action potential behind it as it travels down the axon?

refractory period

How does the capacitance of the multiple layers of membrane in myelin compare with the the capacitance of one layer of membrane of an axon?

capacitance in series adds inversely, so, fortunately, multiple layers have less

Why is the muscle smaller when it is innervated by a nerve damaged by polio?

because the nerve has a trophic effect on the muscle

What happens to the size of the action potential as you go along the axon?

it is all-or-none, always the same

What does "oligo-" in "oligodendroglia" refer to?

a few, each glial cell myelinates a few axons

Conductance to what ion activates late in the action potential?

The late conductance increase is for K+

If multiple sclerosis involves an immune attack on myelin basic protein, and if everybody has this protein in their myelin, how come everybody does not have MS?

rarely does autoimmunity develop

Suppose a cell's resting membrane potential is -60 mV (inside negative). Give a reasonable value for the potential if it received an inhibitory synaptic input causing a graded hyperpolarization.

-65

Explain why propagation of the action potential is unidirectional in terms of the refractory period.

spike cannot triger a spike behind it because that membrane is still not excitable

From the cable equation, we derive properties of the space constant and the time constant. How does that tell us why invertebrates have giant axons?

space constant increases with the square root of the radius

Given that current leaks through capacitors and that membranes have high capacitance, how come myelin, with its many membrane layers does not leak a huge amount of current?

capacitors add reciprocally

For multiple sclerosis, explain autoimmunity (i.e. distinguish it from active immunity against antigens in pathogens).

the antigen is probably a myelin protein

There are cells that look like pseudomonopolar neurons in the dorsal root ganglion (just outside the spinal cord). What function do these cells serve?

sensory input

If you had one size of axon, why would the depolarization 1 mm ahead of a spike be greater with myelin than without (assuming the Schwann cell's myelin is 1 mm long).

Myelin's resistance and capacitance decreases current loss across that distance

What is the toxin from puffer fish that blocks the Na+ channel (and hence the action potential)?

tetrodotoxin

What happens with botulism toxin? (Your answer can be molecular, cellular, or physiological.)

cleave synaptobrevin, block vesicle release, muscles blocked

The conclusion from Loewi's work was that there must be a substance involved. How did his classic experiment show this?

juice from chamber where vagus stimulation slowed heart slows heart in another chamber

Describe the geometry of the input to the spinal cord of the muscle stretch receptor.

cell body is in ganglion as axon goes into dorsal root

If ms (multiple sclerosis) can arise from exposure to myelin basic protein, how come everyone does not have ms?

proteins sequestered from imune surveillance except when there is autoimune disease

Why do they call neurotransmitter vesicles in the process of release "omega figures?

in EM they look like the Greek letter

Ionotropic vs. metatotropic is a way to distinguish neurotransmitter receptors. If muscarinic is metabotropic, what is the corresponding ionotropic receptor for cholinergic transmission?

nicotinic

What is the immediate precursor for dopamine and why is it especially useful as a treatment for patients?

l-DOPA can be given to Parkinson's patients because it crosses the blood brain barrier

What binds to adenylate cyclase to activate so that it makes cAMP out of ATP?

alpha subunit of heterotrimeric G protein

What does protein kinase A (PKA = A kinase) do to the proteins it affects?

phosphorylates them

Once it is activated, what keeps the alpha subunit of the heterotrimeric G protein from running amuck and continuing to activate the next molecule in line in the cascade?

it has GTPase activity then recombines with beta gamma


Where (specifically) is synaptobrevin and what (molecularly) does botulinum toxin do to it?

on vesicle, cleaves (prevents vesicle release)

Reuptake is the predominant mechanism to terminate norepinephrine action. By contrast, how is acetylcholine action ended?

breakdown by AChE

Why might an inhibitor of monamine oxidase (MAO) relieve depression?

potentiate "upper" action of norepinephrine by keeping it around

Why do squids have giant axons? Your answer can be behavioral, it can pertain to the properties of giant axons, or it can be comparative (comparing squid with "higher" nervous systems).

so they can contract their mantle for the escape response synchronously, giant axons conduct faster, invertebrates do not have myelin

Why is salutatory conduction so much faster than conduction without myelin?

all that insulation forces the action potential to jump way ahead to the next node of Ranvier

Why is the prefix "oligo" applicable to olidodendrocytes?

they myelinate several axons in the CNS

"Capacitors in series add reciprocally." What does this say about the capacitance of myelin?

less current would leak out of the axon through the membrane capacitance where there is myelin

By passive spread, a spike at one place depolarizes the axon ahead of it (and behind it) to threshold. Why is conduction unidirectional?

because the sodium channels behind it are inactivated, causing the absolute refractory period

Why might a middle-aged person who had recovered partially from "infantile paralysis" (polio) experience a relapse?

Post polio syndrome has sprouts of motor neurons going away (motor unit goes back to before recovery of function)

An oscilloscope presents the action potential like a graph. What are on the X and Y axes?

X time, Y voltage

Why was Golgi's technique, so exquisitely used by Ramon y Cajal, a contribution worthy of the Nobel Prize?

Among a zillion cells, one cell could be seen in its entirety


this page was last revised 6/17/09

**The muscle lecture

MUSCLE

Fox Chapter 12 (plus references to chapters 5, 7 & 15)

How muscle works molecularly has been a real success story in cell-molecular biology.

Cell structure

Fig. 12.1
Skeletal ("striated" = striped) muscle cell ("fiber" = cell) 10- 100 microns [micro, 10 to the minus 6. meters] (huge) and long (from tendon to tendon)
There are smaller units within fiber called "myofibrils" (1-2 microns in cross section)
Thus 1000-2000 myofibrils/fiber

Fig. 12.6a&b
Sarcomeres are units along the length of myofibrils
Interestingly, the striped (striated) pattern of myofibrils is in register for all the myofibrils in the fiber giving the whole muscle fiber a striated appearance.
Within the myofibrils are the filaments
Actin - G (globular) polymerizes to F (filamentous) actin - the thin filament
Myosin - (2 heavy chains and 4 light chains) - the thick filament
I-band (isotropic - light), A-band (anisotropic, dark) based on actin and myosin, see figure

here is a picture from our histology course, but watch out because the arrows for A, I, and H do not point accurately

Muscle proteins

Fig. 12.8 like last figure
Z disc where actins are joined in the middle of the actins
M line in the middle of the myosin
A (anisotropic)= where myosin is
I (isotropic) where actin is but not myosin
H (helle) (lighter) where there is myosin but not actin
This figure shows titin a gigantic protein that is elastic

"Clinical application" box on p. 356
Muscular dystrophy (Duchenne) X-linked recessive (sex-linked), affects boys
Lethal by age 20
"Dystrophin" protein associated with muscle cell membrane, binding cytoskeleton with extracellular matrix.

Sliding filaments

AFHuxley & RNiedergerke, 1954, Nature
173 971-973
Interference microscopy of living muscle fibers

HHuxley & J Hanson, 1954, Nature 173
973-976 (back to back!)
Changes in the cross-striations of muscle during contraction and stretch and their structural interpretation

Contraction of muscle was well-described in 1958 (H.E.Huxley, The contraction of muscle, Scientific American, Nov. 1958); he is not related to the other Huxleys, Thomas (zoologist and advocate of Darwin), Thomas's grandson, biologist Julian, Julian's brother Aldous, author of Brave new world, and Julian's and Aldous's half brother, Nobelist Andrew F. Huxley whose other work (with Hodgkin) we covered earlier.

Fig. 12.9a&b
Sliding filament explanation of muscle contraction

Fig. 12.21
The length tension curve shows that the optimum is when there is good overlap without the actin colliding (note, there will be an important difference for heart muscle.)

Involvement of ATP

Fig. 12.10
picture myosin as a boat rowing through a sea of surrounding actin molecules.

Fig. 12.12
Interestingly ATP binding unhooks myosin from actin. This can be remembered by thinking about rigor mortis (box p. 348) - a "stiff" in a detective show - has been dead long enough so that ATP has run out and actin and myosin are locked together. ATP -> ADP and a phosphate added to the myosin and this is like the rower back-stroking to get ready to take another power stroke. When the phosphate gets kicked off of the myosin, the myosin and actin bind, followed by the power stroke

Involvement of Ca2+

Fig. 12.14
Ca2+ ions are released to make muscle contract (explained later)
tropomyosin on actin
troponin has a Ca2+ binding site like calmodulin
Ca2+ binding to troponin pulls tropomyosin off of actin's binding sites for myosin

The neuromuscular junction

Fig. 12.3
here is a similar picture from our histology course of the neuromuscular junction
Action potential from nerve opens channels (nicotinic acetylcholine receptors) at "synapse" called the neuromuscular junction. (Notice that the nerve branches.)
This is a big "synapse" and it works.
Here is a transmission electron micrograph of a portion of a neuromuscular junction. Note the folds, increasing the area on the muscle cell. Note the space with electron density in the cleft. Note the numerous vesicles.

Bernard Katz shared the 1970 Nobel prize for using the quantal nature of transmission at the neuromuscular junction. The quanta are individual vesicles. The neuromuscular junction is like any synapse except bigger and easier to study. This information could fit equally well here, in the muscle lecture, or in the synapse lecture (but that was already crowded with Nobelists.

Box in Chapter 7 on page 184
Table 15.10
autoimmune diseases
Myasthenia gravis is an autoimmune attack on nicotinic receptors
Muscle weakness
Here's a picture I found on the web of the eyelid droop
Give AChE (neostigmine) inhibitor neostigmine to ameliorate symptoms

Table 7.5
nicotine is an agonist. there are pharmacological antagonists (curare, a plant alkaloid from Clondodendron tomentosum)
Important for mechanisms of muscular relaxatants used in surgery (like succinylcholine)
Must relax muscles in surgery but must prove that anesthesia is adequate.

The spinal motor neuron

Clinical applications Box on p. 380
Amyotropic Lateral Sclerosis (Lou Gehrig's disease affects spinal motor neurons)
some cases familial led to identification on chromosome 21
coper/zinc Super Oxide Dismutase (SOD1) reduces oxygen radicals
some famous baseball personalities, Lou Gehrig set consecutive games record until broken by Cal Ripken Jr.
Lou Gehrig's farewell speech

Fig. 12.4
(relative to the aforementioned "nerve branches") Motor units
(how many muscle cells per motor neuron)13 eye, 1730 calf

The muscle cell's action potential

Fig. 12.16
Then action potential goes down muscle cell. But cell is too big. So transverse tubules (T tubules) get action potential into cell at numerous locations (for each sarcomere and for each myofibril). Proximity with a specialized smooth endoplasmic reticulum called the sarcoplasmic reticulum causes release of Ca2+.
That "proximity" involves actual interaction of the types of Ca2+ channels in transverse tubules and in sarcoplasmic reticulum.

Fig. 12.19
1 - 1 spike, tetanus for sustained
Note that eventually, fatigue sets in.
A few years ago, in General physiology lab, one of the lab groups obtained the result shown Here. the result when tetanus was obtained by increasing the amplitude of stimulation.

In summary:

ACh to synapse Ecxitation to spike
Final common pathway - motor neuron carries integrated information from nervous system
action potential in membrane and t-tubules, t=transverse
Ca++ release from sarcoplasmic reticulum (ER)
T at A-I junction in Skeletal muscle but it is at the z line in cardiac muscle and in frog skeletal muscle

Types of skeletal muscle:

Difference obvious in turkeys
Fast twitch, strong, anaerobic, white meat
Slow twitch, enduring, aerobic, dark meat
capillaries (hemoglobin), myoglobin, cytochromes in mitochondria
can alter with training
It is possible to stain, in this case for ATPase, to show mixed muscle cells in a muscle (dark is slow, aerobic).

Metabolism:

Fig. 12.24
phosphocreatine (creatine phosphate [backup, battery]) makes ATP using phosphpcreatine kinase

Fig. 12.22
muscle uses glucose and fatty acids (from plasma)
and glycogen and triglyceride (from muscle)

Glycogen -> (glycogenolysis) -> glucose
Overall, 1 glucose can give up to 38 ATP's, a few from glycolysis and the rest from the mitochondrion
Without oxygen, make ethanol (yeast) or lactate (lactic acid).
Anaerobic glycolysis is used to deliver ATP quickly but wastefully (squandering glucose).
Make ATP's but need to regenerate NAD+ [from NADH] to make.

Fig. 5.6
Lactic acid contributes to fatigue in muscle and oxygen debt, and the liver eventually reconverts.
Anaerobic cellular "respiration" is needed in times of extreme exertion because the heart (cardiac output) is the limiting factor in delivery of oxygen to muscle.
Lactic acid is also made by bacteria in yogurt, sour cream, and cheese.

Fig. 16.37
Hemoglobin off-loads oxygen to myoglobin

Monitoring muscle stretch

Fig. 12.27b
remember reflex from synapse lecture
knee-jerk reflex - tap patellar ligament, spindle (stretch receptor, alpha motoneuron to muscle)
gamma motor neuron goes to nuclear chain fibers (intrafusal muscle) to set tone on spindle
sensory fiber wraps around nuclear bag fiber

Smooth muscle

In an undergraduate physiology lab, a piece of rabbit gut is connected to a force transducer. Rhythmic contractions are monitored. Drugs like atropine (see autonomic lecture) slow motility, and this is why it is in anti-diarhea medications. When I was a kid, a teaspoon of some terrible tasting stuff called paregoric cured a belly ache right away, but you can't get paregoric (tincture of opium) any more.

Fig. 12.35 b & c
smooth muscle - arterioles, gut, uterus - involontary, autonomic
actin and myosin are arranged differently (striations helped in sliding filament theory)

Fig. 12.36
Ca2+ comes across cell membrane, not from SR
activates myosin light chain kinase, phosphorylation
phosphorylation (and dephosphorylation) of myosin regulates cross-bridge

Fig. 12.37
regulated by autonomic neurons with varicosities and synapses enpassant
in single unit, autonomic activates then it passes from cell to cell
in multiunit, need to activate each cell

Dr. Fisher is our muscle expert, and he teaches a course in exercize physiology

Exam questions from 2004 - 2008 related to this outline

Shortage of what chemical leads to rigor mortis?

ATP

What is an intrafusal motor fiber?

presets stretch on spindle's stretch receptor

What does a kinase do to a protein?

phosphorylates it

Suppose you are stimulating the nerve to the gastrocnemius muscle. What would BoTox do to the response?

decrease it

When does a spinal motor neuron cause a hyperpolarization at the end plate of a striated muscle cell?

never

In the middle of the dark A band is a lighter H zone. Why is it lighter?

because there is myosin but no actin

What ion, critical to muscle contraction, binds troponin, pulling tropomyosin myosin's binding site on actin?

Ca2+

What is the ATP binding protein in muscle?

Myosin

During exercise, what does the conversion of phosphocreatine to creatine achieve?

makes ATP

During anaerobic metabolism in muscle, what is pyruvic acid converted to?

lactic acid

The sarcoplasmic reticulum calcium release channel is closely related with what channel on the transverse tubule?

a different calcium channel

Several diagrams in your book referred to skeletal muscle fibers as "extrafusal muscle fibers." Why?

to distinguish them from intrafusal in muscle spindle

What happens to the relationship of actin and myosin when ATP binds?

they unbind

While exploring the Amazon, you are shot with a blow-gun dart of curare. What would that do to you?

paralyze

For the monosynaptic knee-jerk reflex, what cell does the sensory neuron of the spindle's stretch receptor synapse onto?

spinal motor neuron

Why is Duchenne muscular dystrophy more common in boys than in girls?

because the mutation is X-linked

What does "striated" mean in the context of striated muscle, and why was the fact that muscle is striated important in developing the sliding filament theory?

striped, helped Huxleys infer actin & myosin properties

Why would it be easier halfway up a chin-up than starting from a position of fully extended arms?

optimal overlap of actin and myosin as opposed to too little overlap

Heart muscle does not follow the length-tension relationship of skeletal muscle. Why is this important?

Fuller ventricle is capable of generating more force of contraction

What treatment would alleviate some of the muscle weakness from autoimmunity to the nicotinic channel?

anti-acetylcholinesterase like neostigmine

Lowering extracellular Ca2+, Katz did his Nobel Prize winning work as he converted the end plate potential to miniature end plate potentials elicited by "quanta." What is the physical appearance of the quantum he witnessed physiologically?

vesicle

The channel carrying the action potential in the T (transverse) tubule is closely linked to what important component in muscle contraction?

sarcoplasmic reticulum (the Ca2+ channel)

What prevents the myosin head from binding actin in striated muscle when a contraction is not called for?

tropomyosin

How would motor units differ in the extraocular muscles (responsible for eye movements) vs. calf (gastrocnemius) muscle?

fewer muscle cells per neuron in muscles for finer movement

Which cell is damaged in ALS (amyotropic lateral sclerosis, Lou Gehrig's disease)?

spinal motor neuron

In smooth muscle, what can phosphorylated myosin light chain do that the unphosphorylated protein cannot?

bind actin

Gamma fibers preset the stretch receptor by causing what specific type of fiber to contract?

intrafusal (or nuclear chain)

What is created from glycogen by glycogenolysis?

glucose (or glucose 6-phosphate)

What type of cell uses phosphocreatine (creatine phosphate)?

striated muscle

If there is lactic acid formation, oxygen debt, and creation of only a few ATPs per glucose molecule, what is this type of metabolism called?

anaerobic glycolysis

Varicosities on autonomic nerves are used to control what kind of muscle?

smooth muscle

Without Ca2+ what does tropomyosin block?

Binding sites on actin for myosin

What transmitter and transmitter receptor are used at the motor end plate?

Acetylcholine nicotinic

Why would curare, by itself, be a poor choice for anesthetizing a patient for surgery?

It is a paralytic, not an anesthetic

In what way does a graph of tension as a function of time look different for complete vs. incomplete tetanus?

Bumpy for incomplete

In what way does smooth muscle's myosin light chain kinase (MLCK) substitute for striated muscle's troponin-tropomyosin complex?

Phosphorylation of myosin allows cross-bridges

Here is a partial list of the proteins of striated muscle: actin, myosin, troponin, tropomyosin. Name another.

titin, dystrophin, myoglobin

What happens specifically when either phosphate or ADP (you pick one) comes off the myosin?

myosin binds to actin and power stroke is taken

One sarcomere goes from the z-line (z-disc) to (where)?

the next z line

How would the H zone look in the biceps at the bottom of a chin-up vs. at the top?

H big at bottom, small at top

T-tubules (transverse tubules) are best known for their channels for which ion?

Ca2+

If you are not active at the time, after a meal, "in times of plenty," glucose is imported into muscle and converted into what?

glycogen

What would happen to the end plate potential elicited by one spike in the motor neuron if the extracellular concentration of Ca2+ in the vicinity of the neuromuscular junction were reduced?

become smaller, become ), 1 or several miniature potentials

By what mechanism does neostigmine help a patient with myasthenia gravis?

increase acetylcholine to better stimulate what is left of the nicotinic receptors

What is the limiting factor that requires the body's muscles to go to anaerobic glycolysis for extreme exertion?

heart's ability to deliver O2

What is the X-axis (abscissa) for the oxyhemoglobin dissociation curve, the graph that shows that myoglobin has a higher affinity for oxygen than hemoglobin?

partial pressure of O2 in mm Hg

What is a nuclear chain fiber used for?

intrafusal muscle to preset stretch receptor

Why can't myosin bind to actin unless it's supposed to?

tropomyosin blocks the sites on actin for myosin binding

Which muscle protein changes configuration, power stroke and back stroke, for muscle contraction?

myosin

Put in order from large to small three alternative, anatomical, words for muscle cell, the subcomponents that make up the cell, and the muscle proteins that make up these subcomponents.

cell=fiber, myofibril, filament=protein

How does the conversion of ATP to ADP affect creatine?

creatine becomes creatine phosphate

What is the function of gamma fibers and their connection to nuclear chain fibers?

preset stretch for stretch receptor

Under the influence of Ca2+-calmodulin, what protein in smooth muscle gets dephosphorylated?

myosin light chain kinase

Give one way the neuromuscular junction is distinguished from the typical synapse in the nervous system.

larger, only excitatory

In terms of the muscle proteins, why is the muscle weaker when it is full length or stretched?

less actin myosin overlap

In terms of muscle proteins, why does the length of the H (helle) zone vary with muscle length?

myosin without overlap with actin

Where is the lactic acid that is built up in muscle taken care of?

liver

Ca2+ channels in the t- (transverse-) tubules are in contact with Ca2+ channels in what subcellular structure.

sarcoplasmic reticulum

What famous drug paralyzes skeletal muscle by blocking the muscle membrane receptor?

curare

What is the cause of the disease of muscle weakness in which nicotinic receptors are lacking?

autoimunity to nicotinic

What enzyme is deficient in familial cases of Lou Gehrig's disease?

Super Oxide Dismutase

How does the oxyhemoglobin dissociation curve explain the offloading of oxygen when blood arrives at muscle?

myoglobin's curve is to the left

Striated muscle's tension (strength) depends on its length. Out of A-band, I-band, and H-zone, which ones change size (as a function of muscle length) and which do not?

A stays the same, I and H would change

Why did they call one muscle protein "dystrophin?"

before they knew anything about function, they identified it as deficient in muscular dystrophy

Calcium ions would indirectly regulate whether ATP is used in muscle. Why wouldn't ATP replace ADP if calcium had not done what it does?

myosin needs to be able to bind actin for that ATP cycle to be able to run

What happens to tropomyosin to allow (or not) muscle contraction?

it exposes (or blocks) binding sites for myosin on the actin

Sir Bernard Katz won his Nobel Prize for demonstrating the quantal nature of transmission at the neuromuscular junction. What happened when he lowered the extracellular Ca2+?

fewer (for instance 0, 1, or 2) vesicles (his quanta) were released

From the depolarization at the nicotinic receptors of the motor end plate, an action potential (using activated Na+ channels) moves down the sarcolemma (muscle cell membrane). That triggers what other channels? (Your answer could state what ion or what cellular component.)

calcium in both t-(transverse)-tubules and sarcoplasmic reticulum

In human surgery (and in animal research), you cannot tolerate muscle movement. Why do you need to be particularly careful about using muscle relaxants?

you need to be certain the patient (or animal) is sufficently anesthetized because paralysis would prevent any communication of distress

What is the significance of myoglobin's curve being to the left of hemoglobin's curve (on the oxyhemoglobin dissociation graph)?

hemoglobin would offload oxygen to muscle

In contrast with the type of cell an alpha motor neuron innervates, what does the gamma neuron connect to?

intrafusal muscle in the muscle spindle

Intracellular Ca2+ is exquisitely orchestrated. In contrast with the calcium binding protein of striated muscle, what is the calcium binding protein of smooth muscle?

calmodulin

Striated muscle has an optimum length, and it's strength (tension) drops off when it is longer or shorter. In what way is the ventricular myocardial muscle strikingly different?

The fuller (more stretched) the ventricle, the more forceful the contraction

Why is a corpse at a crime scene referred to as a "stiff?"

When ATP runs out, actin stays bound to myosin

Why would neostigmine ameliorate the condition of myasthenia gravis?

Shortage of nicotinic channels is somewhat overcome if there is more ACh

What cell is deficient in Lou Gehrig's disease (ALS=amyotropic lateral sclerosis)?

Spinal motor neuron

What are varicosities with respect to control of smooth muscle?

NE is released not so much by synaptic terminals but by many swellings along the axon


this page was last revised 6/25/09

**The autonomic nervous system lecture

Fox Chapter 9 (plus selections from Chapters 7, 8, 14 & 20)

Autonomic n.s.

It's a motor system

Fig. 8.28
Fig. 9.3
motor system for smooth muscle and glands
contrasted with somatic system innervating striated (skeletal) muscle
Autonomic has preganglionic and postganglionic output

Fig. 7.3
Another figure to show the same thing

Parasympathetic and sympathetic

TRANSPARENCY (From an intro book)
Parasympathetic = "rest and digest"
Sympathetic = "fight or flight"

Fig. 9.5 [Fox's version of this same classic figure]
Parasympathetic, cranio-sacral, ACh (nicotinic and muscarinic), ganglion near target
Sympathetic, thoraco-lumbar, ACh (nicotinic) then NE, ganglion near spinal cord

Acetylcholine and Norepinephrine

Fig. 9.7
(same material on next two lines)
Parasympathetic, cranio-sacral, ACh (nicotinic and muscarinic), ganglion near target
Sympathetic, thoraco-lumbar, ACh (nicotinic) then NE, ganglion near spinal cord

Fig. 9.10
(same material on next two lines)
Parasympathetic, cranio-sacral, ACh (nicotinic and muscarinic), ganglion near target
Sympathetic, thoraco-lumbar, ACh (nicotinic) then NE, ganglion near spinal cord

For NE (adrenergic), all receptors are G-protein-coupled-receptors
Alpha (vasoconstriction) phenylephrine (Neosynephrine, nasal decongestant) is agonist
Beta-1 in heart, why beta blockers like propranalol were given for high blood pressure
Beta-2 bronchioles, why asthma inhalers had epinephrine

Fig. 9.5 [again]
Many targets are "push-pull" like heart
Some are unique like arterioles (sympathetic only) -- close in peripheral vascular beds (make hands cold), open in muscle (hyperemia).

Anatomy

Fig. 9.3
arrangement of sympathetic output from lateral horn neuron -> white ramus -> sympathetic ganglion -> gray ramus
Simpler for parasympathetic, i.e. from brain stem nucleus or lateral horn in sacral cord to parasympathetic ganglion
called enteric for gut. Contribution of neural network (plexus) to circular and longitudinal muscles to mediate peristalsis. Parasympathetic allows digestion, sympathetic puts it on hold. Atropine blocks muscarinic synapses and is in anti-diarrhea medications to slow motility.

Beautiful women

Clinical Box on page 253
Atropine muscarinic antagonist
Atropa belladonna (beautiful woman) [deadly nightshade]
SLIDE (Hess, Scientific American, Nov. 1975, p.111) Women are more beautiful with dilated pupils

Channels vs G protein-coupled receptors

Fig. 9.11
use nicotinic and muscarinic to remind you of ionotropic and metabotropic

Heart as an example.

Fig. 14.5
Automaticity at SA and AV nodes (spread from myocardial cell to next myocardial cell). Sympathetic speeds heart, parasympathetic (via vagus, X) slows, and relaxed heart rate is slower than automatic rate.

Male sexual function as an example.

Important aspect of quality of life

Fig. 20.22
(this is not quite true, see below)

Robert F. Furchgott, Louis J. Ignarro, Ferid Murad Nobel 1998 "for their discoveries concerning nitric oxide as a signalling molecule in the cardiovascular system"

A few years ago, I wrote, "This is the only place where parasympathetic affects arterioles, dilating them in corpus cavernosum for erection. Sympathetic contributes to ejaculation."

Then I read a paper by Ignarro and then his Nobel "speech." Actually, for erection (relaxing arteriole smooth muscle), adrenergic (via alpha 1 receptors) contracts smooth muscle, cholinergic (via muscarinic receptors) inhibits adrenergic-induced-contraction (resulting in relaxation); more than cholinergic and adrenergic, a little mentioned autonomic component, the NANC (nonadrenergic noncholinergic) system, mediates relaxation.

In the 2003 movie Something's gotta give, Jack Nicholson has a heart attack while having sex, and the docs ask if he is on Viagra as they are about to give him nitroglycerine. (also listed in advertisements for ED (erectile dysfunction) medications because of interaction and resulting low blood pressure)

People take nitroglycerine for angina (chest pain), and it releases NO (nitric oxide) and relaxes the coronary arteries

Nitric Oxide (NO), made by endothelial nitric oxide synthase (eNOS), unusual in that it diffuses across "postsynaptic" membrane to affect guanylyl cyclase (GC) involved in making cGMP.
NO was endothelial derived relaxation factor (EDRF), mediator of parasympathetic nervous system's dilation of arterioles in corpus cavernosum. Viagra (sildenafil) inhibits the PDE that breaks down cGMP

Exam questions from 2004 - 2008 relevant to this outline

What chemical does Viagra inhibit?

the phosphodiesterase for cGMP

What gas mediates arteriole dilation by the parasympathetic nervous system?

NO (nitric oxide)

A nasal decongestant spray would contain an agonist for what naturally ocurring neurotransmitter?

norepinephrine

The anatomical term "cranio-sacral" refers to what functional unit?

parasympathetic nervous system

For what condition was propranalol, a "beta blocker," given?

high blood pressure

The anatomical term "thoraco-lumbar" refers to what functional unit?

sympathetic

An asthma spray would contain an agonist for what naturally ocurring neurotransmitter?

norepinephrine

Where are nicotinic receptors used in the autonomic nervous system?

ganglia

In addition to cranial nerves, what other nerves make up the parasympathetic nervous system?

sacral

What is the corpus cavernosum?

erectile tissue

Muscarinic receptors are for what neurotransmitter molecule?

acetylcholine

What would sympathetic activation do to the blood flow in muscle?

increase it

Identify one of the two parts of the central nervous system where the parasympathetic output originates. Be specific.

Brain (for cranial nerves) and sacral part of the spinal cord

Propranalol is a btea-1 blocker, and it is given to patients to prevent the action of what neurotransmitter at what site?

norepinephrine in heart

A patient comes in and his heart is stopping because of exposure to malathion. What do you give him?

atropine

Why would atropine be a useful ingredient in medication for diarrhea with cramping?

inhibits parasympathetic meciated activation of gastrointestinal motility

Why are treatments like nitroglycerine contraindicated for men who are on drugs for erectile dysfunction?

An unsafe drop in blood pressure would result from too much smooth muscle relaxation

"The parasympathetic nervous system dilates arterioles in the corpus cavernosum, mediating erection." Give either of the reasons that this statement is not the whole truth according to more modern research.

(1) actually, the parasympathetic nervous system inhibits the sympathetic for this. Also (2) a non-cholinergic non-adrenergic system is of paramount importance.

"Nicotinic" applies to which place (i.e. preganglionic axon terminal, postganglionic synaptic receptors, postganglionic axon terminal, effector receptors)? Justify.

The acetylcholine receptor on the postganglionic cell body

What specific kind of receptor does atropine block?

Cholinergic muscarinic

Where does nicotine have its effect?

on nicotinic acetylcholine receptors most notably in autonomic ganglia

What is the significance of the endothelial cells that line blood vessels in mediating erection?

endothelial derived relaxation factor (EDRF= nitric oxide[NO]) is made there

In which part of the autonomic nervous system is the ganglion near the neuroeffector junction?

parasympathetic

What specific type of receptor mediates the sympathetic nervous system's effects on the heart?

beta-1

Hyperemia, increased blood flow in skeletal muscle, is mediated by what functional subdivision of the nervous system?

sympathetic

How does a nasal decongestant spray like phenylephrine work?

constricts arterioles

Why would a beta blocker like propranalol be given for high blood pressure?

would block beta adrenergic receptors in heart, decrease heart rate and force or volume

How does Viagra work?

inhibit PDE to break down cGMP

What kind of muscle does the autonomic nervous system connect to?

smooth

Usually your eye care professional will administer something to dilate the pupils. What type of receptor for what neurotransmitter is blocked?

muscarinic for acetylcholine

For which component of the autonomic nervous system is the ganglion closer to the central nervous system?

sympathetic

Explain how vasoconstriction (or the opposite) applies to how a decongestant unclogs a stuffed nose.

An alpha agonist like phenylephrine constricts engorged vascular bed

"Control of arteriole smooth muscle involves "unique" innervation, sympathetic only. Except for (what?).

arterioles to the corpus cavernosum

"This and other erectile dysfunction medications should not be taken if you are taking nitrates for chest pain." Why not?

the combined actions, all causing relaxation of arteriole smooth muscle, would cause an unsafe drop in blood pressure


this page was last revised 6/25/09

**The energy lecture

Energy metabolism

Readings
Fox selections from Chapters 2, 4, 5, 6, and 11

"He said science was going to discover the basic secret of life someday," the bartender put in. He scratched his head and frowned. "Didn't I read in the paper the other day where they'd found out what it was?"
"I missed that," I murmured.
"I saw that," said Sandra. "About two days ago."
"That's right," said the bartender.
"What is the secret of life?" I asked.
"I forget," said Sandra.
"Protein," the bartender declared. "They found out something about protein."
"Yeah," said Sandra, "that's it."

-Kurt Vonnegut, Jr. Cat's Cradle

Overview

We will not get very technical on biochemistry of metabolism, since this is a physiology course and not a biochemistry course.

Reminder
Metabolism is the general term for two kinds of reactions:
(1) catabolic reactions (breakdown)
and
(2) anabolic reactions (constructive)

Organic Chemistry is the chemistry of carbon (C) which makes 4 bonds.
In "Star Trek" (the first movie), people were called "carbon based units" by the alien.

Carbohydrate

Fig. 2.13a
Carbohydrate (Carbo-hydrate is also sort of a compound word, carbon, "hydrate" suggests water) - the general formula is Cn(H2O)n
Monosaccharides
Hexose (hex = 6 [carbons], "-ose" always means sugar)- glucose, the most famous monosaccaccharide, is good to illustrate that monosaccharides usually assume a ring structure

Fig. 2.15
Compound dehydration synthesis puts sugars together
Hydrolysis (hydro-water, lysis-breakdown) is the opposite.
In digestion, macromolecules are broken down to monomers.
Disaccharide - sucrose, lactose (milk)
Figure shows maltose and sucrose, and shows dehydration synthesis.

Fig. 2.14
Polysaccharides starch (plant), glycogen (glyco-sugar, gen-give birth to) (animal)
Energy storage:
In liver for whole body
In muscle for muscle use

Fat

Fig. 2.19
Lipids (fats) store more energy (2x sugar) 1 tablespoon of sugar is 50, fat 100 "Calories" = kilocaloriies
Glycerol & 3 fatty acids (16-24 C long) - triglyceride ester bonds , note the dehydration synthesis
The -COOH defines an organic acid such as a fatty acid, otherwise the molecule is a hydrocarbon.
C-C (single bond) vs. C=C (double bond) unsaturated (vs saturated with H's), with several, it is referred to as "polyunsaturated" PUFA = polyunsaturated fatty acid
Animal fats tend to be saturated, bad for arteries leads to atherosclerosis; vs vegetable fats better.
Polar phospholipids - we'll talk about that later, because our emphasis now is energy.
Steroids-cholesterol & hormones - we'll talk about that later, because our emphasis now is energy.
Salts of cholesterol are in bile (from liver) that acts like a detergent to emulsify fats to aid in digestion.

Protein

Fig. 2.27
short = "Peptides", medium = polypeptide, long = "protein" (hundreds, thousands of amino acids)
The general formula is NH2-CR-COOH - amino ( -NH2 ) and acid ( -COOH ).
Peptide bonds involves -NH2 and -COOH getting linked with a dehydration synthesis.
There are about 20 amino acids (alphabet of 20 letters)
R group varies, see figure.
About half of the amino acids are "essential" meaning that they cannot be made by metabolic conversion from other molecules and thus need to be eaten
Structure:
1. primary (the sequence)
2. secondary (alpha helix, beta pleated sheet)
3. tertiary structure (disulfide and other bonds)
4. quaternary structure (chains interact with each other)
Here is a really important example - hemoglobin - which has 2 alpha subunits and 2 beta subunits and a heme group.

Figure 5.16
Important to the topic of energy in physiology, amino acids can be used for energy, nitrogenous waste must be eliminated as urea.

Biological energy

Fig. 4.15
ADP plus phosphate <-> ATP involved in storage and release of energy [typo on transparency, but o.k. in book]
ATP made of Adenine, ribose and 3 phosphates, energy stored in 3rd phosphate bond
It is interesting to note that ATP delivers it's energy by transferring its phosphate to molecules (you will see this several times in diagrams throughout the semester)

Energy - kinetic and potential (discussing bioelectricity, potential will also be Volts)
BTU's (British thermal units, which can be converted to calories) imply that energy and heat are related.
Heat stored in energies of covalent bonds in kcal / mol
Free energy can be used for work = what is stored in bonds minus what is wasted as heat
cellular respiration C6H12O6 -> 6CO2 +6H2O + energy
the free energy is 686 kcal/mol
ATP to ADP
38 of them generated when respiration is complete
40.3% efficient, the rest is heat, usually considered as waste but useful in temperature regulation in warm blooded animals, homoiotherms, homeotherms.

Reminder - "count" "calories"= kcal
2000 per day for a sedentary adult woman
Important that we do not lose calories (through urine or feces) except through urine in untreated diabetes.
Marathon - 3000 Cal aerobic. 100 yd dash -anaerobic

We get our energy mostly from (1) glucose, (2) glycogen (glyco-sugar, gen-give rise to) in muscle for use in muscle and in liver for glucose release to blood, (3) amino acids (with NH3 as waste), or (4) fat (mostly fatty acids are chopped down 2 carbons at a time to give acetic acid into acetyl CoA in the Kreb's cycle).
Photosynthesis to make glucose, cellular respiration to release energy
Reaction [for glucose, C6(H2O)6]: C6H12O6 + 6 O2 -> 6 CO2 + 6 H2O
Overall, 1 glucose can give up to 38 ATP's, a few from glycolysis and the rest from the mitochondrion

Glycolysis and anaerobic glycolysis

Background
It is important to introduce NAD+ plus 2 H <-> NADH in oxidation - reduction reactions as a way to carry electrons.
lose electrons - oxidation (NAD+ is oxidized)
nicotinamide adenine dinucleotide
add electrons - reduction (NADH is reduced)

Fig. 5.3
Glycolysis is a compound word glyco-sugar, lysis-splitting. Glucose is split into 2 pyruvic acids
Use 2 ATP's make 4, net 2 make 2 NADH's plus 2 H+'s, the H+'s come from from "sugar"

Fig. 5.4
This was covered in muscle lecture
without oxygen, make lactic acid.
Anaerobic glycolysis is used to deliver ATP quickly but wastefully (squandering glucose).
Make ATP's but need to regenerate NAD+ from NADH to make.
Lactic acid contributes to fatigue in muscle and oxygen debt, and the liver eventually reconverts.
Anaerobic cellular "respiration" is needed in times of extreme exertion because the heart (cardiac output) is the limiting factor in delivery of oxygen to muscle.

Fig. 5.5
Polysaccharides
Glycogen - animal starch, polymer of glucose
High in muscle where it provides glucose for local use
High in liver where it provides glucose when fasting
Cellulose - cannot digest - "fiber"

Regulation by the hormone epinephrine (adrenalin)

Fig. 11.10
Epinephrine involved in stimulating liver to release glucose
Earl W. Sutherland, Jr. (from the US) won the 1971 Nobel Prize for mechanisms of hormone action.
It pertained to that beta adrenergic part and cAMP, a "second messenger" or part of a signal transduction "cascade."
So Sutherland is sometimes considered the founder of "signal transduction."
Note that there is a separate alpha adrenergic effect too

Glycolysis and the Kreb's cycle

Fig. 5.12
Pyruvic acids generate 2 acetic acids, become Acetyl CoA's.
Kreb's cycle = citric acid cycle = TCA (tricarboxylic acid cycle)
Takes place in the mitochondrion
A few ATP's are made plus NADH's and FADH2 are generated
CO2 is generated here.

The1953 Nobel prize in Physiology and Medicine was divided equally, one half awarded to: SIR HANS ADOLF KREBS for his discovery of the citric acid cycle and the other half to: FRITZ ALBERT LIPMANN for his discovery of co-enzyme A and its importance for intermediary metabolism.

sugar-H2 + NAD+ -> (DEHYDROGENASE) "sugar" + NADH + H+
(in other words, H is split to H+ and e-)
Electron transport and oxidative phosphorylation use oxygen
cytochromes - these are iron - containing pigments (iron is in the form of heme)
NADH and FADH2 give electrons to cytochromes and oxygen

Protons pumped, then flow down gradient making ATP's.
Something like an ion pump (we will covered that later in the semester) in reverse is how most ATP is made, H+ (pH, proton) gradient runs through that molecule, like water running through turbines generating electricity, to generate ATP

How does glucose get into the cell?

Fig. 6.16
Facilitated diffusion for glucose transport

Fig. 6.17
Insulin causes glucose transporters to be inserted to the membrane

Fig. 6.20
There is another kind of glucose transporter where Na+ (already pumped with ATP) drives it

Fig. 11.11
The receptor for insulin is a membrane spanning tyrosine kinase that dimerizes
Kinase means that the enzyme phosphorylates a protein
Tyrosine refers to the fact that phosphorylation is on tyrosine (an amino acid) residues.
Obviously, this would take place on the intracellular side of the membrane

Questions from 2004 - 2008 tests that pertain to this lecture

What does a kinase do to a protein?

phosphorylates it

How does glucose get into a cell?

you need a membrane protein for diffusion

What is the activity of the insulin receptor enzyme?

tyrosine kinase

What is the polymer of glucose that is so important in muscle and liver metabolism?

glycogen

How is it that facilitated diffusion of glucose is increased by insulin?

more GLUT4 transporters deployed to membrane

The opposite of dehydration synthesis (condensation reaction) happens in digestion. What is this called?

hydrolysis

About how many ATPs do you get from full aerobic metabolism of one glucose molecule?

38

During anaerobic metabolism in muscle, what is pyruvic acid converted to?

lactic acid

What is the function of salts of cholesterol made by the liver and secreted into the small intestine?

emulsify fats

When I remind you that the insulin receptor is a tyrosine kinase, where is tyrosine and what happens to it?

on intracellular side of enzyme, tyrosine (amino acid) becomes phosphorylated

What second messenger activates protein kinase when the beta-adrenergic receptor of a liver cell binds epinephrine?

cAMP

In your body, what becomes of the amine of an amino acid if you use that amino acid for calories?

becomes ammonia that gets converted to urea

In your digestion, macromolecules are hydrolyzed. What is the name of the opposite reaction that had been used to string together monomers into a polymer?

dehydration synthesis

Arachidonic acid has 4 double bonds. What is the term for such a molecule?

polyunsaturated fatty acid

While fasting, what does the liver do with the glycogen it stores?

breaks it to glucose and sends that to the blood stream

How many pyruvic acids do you get from one glucose?

2

If a fatty acid were 14 carbons long, how many acetyl co-A's would be delivered to the Krebs cycle if it were chopped down completely in catabolism?

7

Epinephrine, acting on the beta adrenergic receptor, causes what to happen to glycogen in the liver?

breakdown to glucose and release to bloodstream

In addition to facilitated diffusion, there is a transport mechanism for glucose requiring energy delivery from ATP. To what molecule does ATP deliver its energy?

the sodium pump

In the biosynthesis of fat, to attach a fatty acid to glycerol via an ester bond, what molecule must be removed?

H2O

Fatty acids are "chopped down" two carbons at a time to feed into metabolism. Where do these two carbon components feed in (biochemically)?

acetate (acetyl CoA)

The need to regenerate NAD+ from NADH causes the formation of what from pyruvic acid?

lactic acid

What molecules are generated from the complete aerobic cellular respiration of glucose (in addition to energy)?

H2O and CO2

What are the salts of cholesterol of bile used for?

emulsify fats in digestion

Chemically, how is a polyunsaturated fatty acid different from a fully saturated fatty acid?

Double C=C bonds

What do we have to get rid of if we use amino acids for energy?

Nitrogenous waste

The hormone epinephrine (adrenalin) is sometimes considered the "first messenger" to signal the liver of the need to release glucose. Within the liver cell, what has been called the "second messenger" in this signal transduction cascade?

cAMP

What is urea made from and where does the body make it?

NH3 and CO2 in the liver

Describe the structure of hemoglobin in terms of protein subunits and the units where iron is located.

2 alpha and 2 beta protein chains each with a heme group

How is it that a liver secretion can emulsify fats to aid in digestion?

salts of cholesterol would have hydrophilic and hydrophobic sides

On the way to the Kreb's cycle, fatty acids are chopped down two carbons at a time to make what?

acetic acid or acetyl coA

"H is split to a proton and an electron." To achieve what?

to drive proton pump then capture energy of proton pump to make ATP

How can a cell's ability to take up glucose be so different with vs without insulin?

insulin causes the membrane deployment of transporters

What molecule donated the phosphate when insulin prompted the insulin receptor dimer to phosphorylate itself?

ATP

What would a beta adrenergic receptor on a liver cell mediate?

glycogenolysis

For one type of glucose transporter, not the facilitated diffusion, energy is required. How is that energy delivered?

when glucose is cotransported with Na+, the sodium pump

Carbon dioxide plus (what?) are converted into urea in the liver.

ammonia (NH3)

Polymers (macromolecules) are constructed from their building blocks by (what process)? (the opposite of how they are broken down in digestion)

dehydration synthesis (as opposed to hydrolysis)

"Salts of cholesterol" - relate to digestion. (Your answer could refer to an organ or a process.)

from the liver into the duodenum (small intestine) to emulsify fat

Sutherland's Nobel Prize winning work had cAMP as the "second messenger." For the "first messenger," what is the type of receptor on the surface of the cell?

beta adrenergic

How does fat feed into metabolism to render ATP? (An answer for either type of components that make up a fat will be OK.)

glycerol gets converted to the precursor of pyruvic acid. Fatty acids get chopped down 2 carbons at a time to become acetyl CoA

"You're not going to get carbon dioxide from anaerobic glycolysis" because it is made in what specific step?

Krebs cycle

Why would you ultimately need energy (ATP) for one type (which type?) of glucose transporter?

the one that uses sodium ions running down their concentration gradient - those ions need to get pumped back out

What use is made of protons (H+, hydrogen ions) running back down their concentration gradient (after they had been pumped up that gradient)?

This is the "water turbine" to generate ATP

"Tyrosine kinase" - where did the phosphate come from?

ATP donates the phosphate there (and pretty much everywhere)

Amino acids can be used for catabolic energy. Where do they feed into the metabolic mill?

Into pyruvic acid just before acetyl co-A

What would a beta adrenergic receptor on a liver cell mediate?

Via cAMP, increase conversion of glycogen to glucose

this page was last revised 6/25/09

**The metabolism lecture

Control of metabolism, Fox, Chapter 19 (also some other chapter figures, 11 and 3)

General considerations

Control of energy metabolism is so important that there are two major hormones (insulin and glucagon, proteins from the pancreas), as well as many others (thyroxine, epinephrine, and cortisol) to regulate it on short- and long-term bases.

In a lab...

...(BL A347, Fall, 2004), we injected insulin into mice, decreasing glucose, then injected glucagon, bringing it back up. Data: before: 157 mg/dl. after insulin 49, after glucagon 197.

More on insulin and glucagon

Fig. 11.29
In pancreas, which is largely a digestive exocrine gland, there are also islets of Langerhans (as shown in this picture from our histology course) which are the endocrine glands where the beta cells make insulin and the alpha cells make glucagon

Fig. (like 11.31a)
Pancreas Insulin- sugar uptake into cells (blood sugar down), make glycogen in liver

Fig. 3.23
2 peptides clipped from one chain held by disulfide bonds
(this sort of processing is common for signalling molecules)

Diabetes mellitus

Type 1 autoimmune disease beta cells are destroyed, young people, insulin dependent
inject insulin. protein, must inject
(vs steroid like "the pill" which can be taken orally)
Type 2, older people, genetic, correlated with overweight, non-insulin dependent
sugar in urine- can't pump back, in our physiology labs, we use these urinalysis strips which include a test for glucose in the urine. In the aforementioned endocrine lab, we introduced the students to this type of strip and meter for testing blood glucose.
Eye problems (too many new blood vessels - angiogenesis) and cardiovascular problems
Brain is not insulin-dependent - coma from too much insulin because no glucose for brain
Glucagon mobilize sugar to blood like adrenalin
sugar regulates insulin and glucagon

Glucose (and other calories)

Review

Fig. 19.2
Fat, carbohydrate and protein feed into metabolism
What you may not have seen before this figure is ketone bodies, produced from fatty acids in liver.
Low carbohydrate diet and diabetes can lead to ketosis, even ketoacidosis.
Note also that this figure shows that urea is the nitrogenous waste from using amino acids for calories.

Fig. 11.31
Blood glucose up, insulin up, glucagon down, cells use glucose
Blood glucose down, insulin down, glucagon up, glycogenolysis & gluconeogenesis (making of glucose from molecules like amino acids.

Fig. 19.10
The above is given in more detail relative to after meal vs fasting

What the liver does

Fig. 19.9
Here's what the liver does to release:
glucose (from glycogen and amino acids)
and
ketone bodies (from fat and amino acids)
When you fast, fat and muscle are broken down

Fig. 19.7
Opposite when insulin (and glucose) are plentiful:
Fat deployed (and not released) from adipose tissue
and
Glycogen deployed (and glucose not released) from liver

How glucose is monitored

Fig. 19.8
How glucose is monitored by a beta cell
glucose is transported in by GLUT2
metabolism makes ATP
ATP is ligand that closes K+ channel
cell depolarizes
voltage gated Ca2+ channel lets in Ca2+
exocytosis from vesicles with insulin

Signal transduction

Fig. 11.11
Insulin receptor is tyrosine kinase
a dimer
crosses membrane
binds insulin extracellularly
puts phosphates on tyrosine residues

Fig. 19.14
Like for epinephrine, receptor for glucagon is G protein coupled receptor
For the umpteenth time, I show you signal transduction cascade
One fact on this figure not shown before:
cAMP acts by binding inhibitory subunits and pulling them off catalytic subunits of PKA
The kinase phosphorylates enzymes, activating some and inhibiting some
end result, of course, is glycogenolysis in liver and lipolysis in adipose tissue

Glucocorticoids

Fig. 19.15
Glucocorticoids are also involved in stress (mobilizing molecules for catabolism)
Glucose, fatty acids, ketone bodies and amino acids in blood increase.
This is slower than for epinephrine

Test questions from 2004 - 2008 that relate to this outline

What is the ligand that closes the K+ channel in the beta cell's mechanism for monitoring glucose?

ATP

What is the activity of the insulin receptor enzyme?

tyrosine kinase

What is the polymer of glucose that is so important in muscle and liver metabolism?

glycogen

In the process where epinephrine causes glucose release from liver, what enzyme does cAMP activate?

protein kinase A

In fasting, gluconeogenesis can provide some glucose from amino acids. Where do these amino acids come from?

muscle

If you had a lot of ketone bodies, what does that tell you about what is going on in your metabolism?

you are using fats, probably fasting

How is glucose detected by b cells in the islets of Langerhans?

being metabolized to make ATP, ligand for channel

Insulin injected into an anesthetized mouse would decrease blood glucose. What other hormone, normally produced in the islets of Langerhans, would raise the glucose levels back?

glucagon


When I remind you that the insulin receptor is a tyrosine kinase, where is tyrosine and what happens to it?

on intracellular side of enzyme, tyrosine (amino acid) becomes phosphorylated

Epinephrine, acting on the beta adrenergic receptor, causes what to happen to glycogen in the liver?

breakdown to glucose and release to bloodstream

In addition to facilitated diffusion, there is a transport mechanism for glucose requiring energy delivery from ATP. To what molecule does ATP deliver its energy?

the sodium pump

The insulin receptor dimerizes when it binds insulin. What do these molecules do that gives them the description "tyrosine kinase?"

they phosphorylate the amino acid tyrosine

If you need to take insulin, why do you need to inject it?

if you ate it the protein would be broken down

As it applies to diabetic retinopathy, what is angiogenesis?

formation of new, fragile, blood vessels

What holds the two peptide chains of insulin together?

disulfide bonds

What process is mediated by the entry of Ca2+ into the pancreatic beta cell?

release of vesicles

What allows the return of the inhibitory subunit to the catalytic subunit of protein kinase in the signal transduction pathway for glucagon?

conversion of cAMP to 5'AMP

Under what circumstances would ketone bodies be released from the liver?

fasting

What would insulin cause an adipose cell to do?

take up glucose

What donates the phosphate when the insulin receptor gets phosphorylated?

ATP

"Insulin is a receptor tyrosine kinase." Receptor - it is a receptor molecule." Kinase - it is an enzyme that phosphorylates proteins. What does the word tyrosine imply?

it is the amino acid that gets phosphorylated

Why can't you just swallow insulin (instead of injecting it)?

would be broken down in digestion

How is cAMP made? (Answer either [1] what is the precursor? or [2] what is the enzyme?)

ATP -> adenylyl cyclase

Facilitated diffusion for glucose transport does not utilize ATP. Under what circumstances does ATP get used for glucose transport?

Indirectly, Na+K+ATPase, to let Na+ drive co transport in kidney tubule and gut

What would an injection of glucagon do to the blood glucose level?

raise it

I repeated the point "Insulin increases glucose transport into cells in insulin-dependent tissues like liver, muscle and adipose tissue." What is the most important non-insulin-dependent part of the body?

brain

What is gluconeogenesis?

forming glucose from other molecules such as amino acids

What special job is there for the ATP that is generated by glucose metabolism in the beta cell of the islets of Langerhans?

ATP is ligand that closes K+ channel to depolarize cell

What is released from adipose tissue under the influence of glucagons?

fatty acids

Give one phrase to describe Type 2 diabetes.

non-insulin dependent, correlated with overweight, affecting receptor, occuring at a later age

What happens to the translated amino acid sequence to make the final insulin hormone?

part gets cleaved off, 2 chains linked by disulfide bridges

Why would the physician deliberately burn holes in the retina (laser photocoagulation)?

to decrease angiogenesis in diabetes

If the insulin/glucagon ratio favored gluconeogenesis, what would be happening to the insulin dependent cellular uptake of glucose?

decrease

Under what circumstances would muscle be broken down for energy?

fasting

With respect to your eating habits, when would ketogenesis occur?

fasting

What happens to the membrane voltage when glucose signals a beta cell in the islet, and how is ion flow affected to cause this electrical change?

depolarize, K+ flow decreased

How does cAMP activate PKA?

pull inhibitory subunits off catalytic subunits

What is the circuitous route by which cortisol causes the increase in blood glucose?

muscles release amino acids that are converted to glucose in the liver

What is proinsulin, and how is this processed to make the active hormone?

It is a longer polypeptide, a chunk is chopped out of the middle, and the two parts of insulin are tied together by disulfide bonds

How does destroying part of a diabetic's retina preserve vision?

It decreases the signal for angiogenesis

During fasting, what will happen to the level of ketone bodies in the blood?

increase

What hormone promotes the storage of triglyceride into an adipose cell?

insulin

How, specifically, is Ca2+ involved in how beta cells put out insulin?

When the beta cell depolarizes (ATP closes K+ channel) Ca2+ comes in, involved in insulin vesicle release

he "water turbine" to generate ATP

"Tyrosine kinase" - where did the phosphate come from?

ATP donates the phosphate there (and pretty much everywhere)

Amino acids can be used for catabolic energy. Where do they feed into the metabolic mill?

Into pyruvic acid just before acetyl co-A

What would a beta adrenergic receptor on a liver cell mediate?

Via cAMP, increase conversion of glycogen to glucose

What pancreatic hormone is increased during fasting?

glucagon

"ATP is the ligand that closes the K+ channel in the islet's beta cell." What does this do to the electrical potential?

depolarize

What effect does cortisol have on adipose tissue?

Cause release of free fatty acids


this page was last revised 7/1/09

Circulation

Fox Chapters 13 and 14 (a figure from chapter 12)

Overview

In multicellular metazoan, need a vascular system (in terestrial plants above mosses, xylem and phloem)
Circulation : Cardiovascular system

Anatomy of the heart

TRANSPARENCY (Review, Introductory Biology)
Fig. 13.10
Chambers of heart
Birds and mammals have 4 chambers
Note that right is drawn on left as if looking into the chest of a supine subject (as I first mentioned when I lectured on Loewi's discovery of vagus stuff, acetylcholine)

Here is the circuit: LA - LV - Arteries (aorta, etc.) (blood pressure taken here) - Arterioles (regulate blood flow to muscles, brain, digestion, kidneys and skin) - Capillaries (near, exchange, WBC's) - venules - veins (no pressure, valves)- RA - RV - Pulmonary arteries - Lung capillaries - Pulmonary veins -

Heart valves and sounds

Fig. 13.11b
pulmonary valve (semilunar) feeds pulmonary arteries
aortic valve (also semilunar) feeds aorta
These valves snap shut from arterial back pressure at the end of systole to make second heart sound- "dub"
Superior and inferior vena cava feed right atrium -> ventricle via tricuspid (atrio-ventricular) valve.
Pulmonary veins feed left atrium -> ventricle via bicuspid (atrioventricular) valve.
Tricuspid & bicuspid snap shut at start of ventricular contraction to make first heart sound- "lub."
If there is backslosh through valves, this is called a heart murmur.

Blood vessels

Fig. 13.26
artery is like hose
blood flow to emptying into vascular bed: regulation by smooth muscle of arteriole
capillary is one layer of endothelial cells (fenestrated or continuous)

TRANSPARENCY (Review, Introductory biology)
Fig. 14.25
- blood spreads out as it goes from arteries -> arterioles -> capillaries and hence moves slower. Pressure goes down during movement arteries -> arterioles -> capillaries (bottom).

Fig. 13.30
Blood moves slowly and with very little pressure in veins. Movement in veins is mostly passive with a series of valves and where contraction of skeletal muscles helps

Fig. 13.37
Lymphatic circulation helps to percolate interstitial fluid back to circulation

Fig. 14.23
Shunts (arteriovenous anastomoses) help to regulate circulation through peripheral vascular beds.

Cardiac cycle and blood pressure

Fig. 13.13
cardiac cycle
Diastole (between heart beats), systole is during ventricular contraction, hence terms systolic and diastolic blood pressure.

Fig. 13.14
Ventricle fills during diastole.
Ventricle empties during systole.
Ventricular pressure builds during systole.

Wiggers diagram.
Relates ventricular pressure to arterial pressure.
Pulmonary pressure is lower than systemic.
Buildup of ventricular pressure opens valve and blood moves to aorta.
As ventricle relaxes, back pressure from artery snaps valve shut.

Ventricular filling

Fig. 14.2
Frank-Starling law.
The greater the ventricular filling, the greater the cardiac output.
This is good! -- recall that the tension length relationship for striated muscle had a peak, but, if the muscle got too long, less force could be generated.
This figure also shows that the sympathetic nervous system moves this curve up.

Measuring blood pressure

It is arterial blood pressure that is usually measured.

Fig. 14.30,
Fig. 14.31
close off artery, when it opens (systolic pressure), blood flow is turbulent and noisy (Korotkoff sounds), when it is always open (diastolic pressure), blood flow is no longer noisy
Blood pressure is measured in arteries
High blood pressure is called the "silent killer."
hypertension 45 million Americans - salt intake is still debated, >140/95 high 140/70 normal
high diastolic is especially bad

Explained by Wiggers diagram, if diastolic b.p. is high, then it takes higher ventricular pressure before valve opens and blood actually moves.

Regulation of blood pressure

Fig. 14.27
Blood pressure is regulated by sensory receptors in aortic arch and carotid sinus.
Goes to medulla oblongata of brain theh out to sympathetic and parasympathetic nervous systems.
There are also brain influences that come down via hypothalamus.

Myocardial cells

Fig. 12.32
Heart muscle cells branch and come together and are joiined at intercalated discs with gap junctions that spread the electrical signal from cell to cell.

cardiac muscle - automatic (explained below)
here is a picture from our histology course of heart muscle cells joined at intercalated discs
(like Figure 12.34)

Electrical activity of heart cells

Fig. 13.20
Electrical - SA (sinoatrial) node (or electrical pacemaker) - spread - automatic.
Sympathetic nervous system speeds it up, parasympathetic nervous system slows it down.
AV (atrioventricular node) is eventually stimulated.
If it were not, it is also automatic but slower and would generate a heart beat in the venticals.
Bundle of His, bundle branches, and Purkinje fibers get ventricular depolarization to happen almost synchronously.

Fig. 13.18
Pacemaker cells have depolarization during diastole because of slow Ca2+ channels.
Pacemake potential-HCN=hyperpolarization cyclic nucleotide (beta-1 adrenergic affects cAMP)
Spike is from Fast Ca2+ channels and Na+ channels
Repolarization uses K+ channels.

Fig. 13.19
Ventricular myocardial cells have long action potentials involving the specific channels shown.

The ECG

Fig. 13.24
Einthoven's triangle to show possible placement of EKG (ECG = electrocardiogram) leads.
Because a lot of cells in heart work together, and because extracellular fluid has high conductivity, electrical activity can be recorded non-invasively.

Fig. 13.22b
P is atrial depolarization.
QRS is ventricular depolarization.
T is ventricular repolarization.

Fig. 13.25
This figure relates EKG to pressure and sounds

Atherosclerosis

Fig. 13.26
(again)
Normally artery has
tunica externa
tunica media
tunica interna (endothelium and elastic layer )

Fig. 13.32
A layer of fat with ccholesterol between media and externa
ulceration lining lumen
atherosclerosis - hardening of the arteries - plaques
atheroma with macrophages
Cholesterol is a problem

Heart attack

General:
Myocardial cells not regenerate (by mitosis in the adult). This is why heart attack is so damaging. The same is true for the nerves in the central nervous system where similar damage is called stroke.
Coronary arteries clog -> myocardial infarction - coronary thrombosis - ischemia (too little blood flow for oxygen delivery)
Angina, chest pain, and referred pain

Platelet aggregation - thrombus (local), embolism (from elsewhere) cause ischemia
tissue plasmogen activator (TPA) dissolve clots
streptokinase thru catheter dissolve clot
aspirin inhibits clotting, coumaden is a strong anticoagulant
catheter with balloon angioplasty insert stent

fibrillation - CPR (keep brain alive, needs O2)
In CPR (cardiopulmonary resuscitation) chest pressure keeps blood flowing a little and rescue breathing keeps blood oxygenated
1 million Americans die/yr reducing since 1971
bypass operations, replace coronary artery with vessel from somewhere else in the body, there are 100,000-200,000/yr operations - 30% may be unnecessary

"heart attack" - myocardial infarction
heart muscle is aerobic
anaerobic metabolism would build up lactic acid and cause pain (angina pectoris)
nitroglycerine relaxes smooth muscle (Viagra and other ED medications would be contraindicated)
heart muscle damage by necrosis (as opposed to apoptosis - programmed cell death)
can be detected in S-T of ECG
uncoordinated contraction of heart muscle - fibrillation
in atria fibrillation is not so important becaus atrial beat only addis a little bit to ventricular filling
in ventricles, it is fatal and hence the importance of defibrillators
re-entry of excitation as electrical signal takes long route around scar tissue after heart attack can contribute to poor ventricular coordination

Risk facrors for heart attack
(1) High blood pressure (the silent killer) -- Wiggers diagram --heart has to work harder to open semilunar valves.
(2) prior heart attack
(3) smoking
(4) diabetes
(5) family history - a dominant allele in hypercholesterolemia (and other genetic factors?)
(6) LDL-low density lipoprotein - made in liver - low LDL receptors help liver take up cholesterol
LDL receptors take out cholesterol which otherwise deposits
HDL may lower deposition - excercise good for this
(7) clotting, especially clumping of platelets) inhibited by aspirin (and coumadin) - hence term "coronary thrombosis" (in coronary artery)

Prevention -
(1) exercise - increase HDL (endothelial cells do not take up)
(2) antioxidants (oxidized LDLs in endothelial cells are bad)
alcohol in moderation (but people who die of cirrhosis rarely have atherosclerosis)
statins (box on p. 412):
(a) block rate limiting step in cholesterol synthesis in liver
(b) secondarily increase LDL receptors

Readings

S. Cohen J Leor Rebuilding broken hearts, Scientific American, November 2004, 44-51

infarct kills cardiomyocytes
noncontractile fibrous cells replace
adjacent healthy myocytes may die
(remodeling)
ventricle wall becomes thinner, distends, might rupture
heart failure
tissue engineering - must have scaffold for cells and blood supply
3-D sponge-like frame made alginate (from algae) frozen
progress so far- can prevent further damage
add controlled release microspheres of growth factors to help angiogenesis

Pacemakers (keep the beat) [working knowledge] M Fischetti, Scientific American, November 2004

wires run in through vein
tips have steroid reservoir to block early inflammation
that keeps contacts healthy
ICD - Implantable cardioverter defibrillator


Exam questions from 2004 - 2008 that relate to this outline:

When, in the heart cycle, do the bicuspid and tricusid valves snap shut?

at the beginning of ventricular contraction

What kind of blood vessels have the highest TOTAL cross sectional area?

capillaries

What does the last Korotkoff sound signify?

the diastolic (arterial) blood pressure

What are the cells that line blood vessels including capillaries called?

endothelial cells

Why is the wall of the ventricle thicker than the wall of the right ventricle?

systemic circulation is higher pressure than pulmonary

What is Einthoven's triangle?

Hook-ups for diagnostic EKG Leads I, II, and III on 2 wrists and left ankle

Long QT Syndrome, diagnosed by a lot of time between the QRS and the T, affects a channel (for what ion?) involved in the repolarization of ventricular myocardial cells?

K+

Cells in what areas depolarize automatically during diastole?

SA node

Although the electrical signal would pass from one myocardial cell to the next, specialized fibers hurry it to much of the ventricular muscle synchronously. What are these fibers?

bundle of His, bundle branches, Purkinje fibers

Why would you die of if there were too much time between heart failure and defibrillation without CPR (cardio-pulmonary resussitation)?

brain would die without O2 (and glucose)

The time between the QRS and the T represents the duration for what specific cell type?

ventricular myocardial cell

For a normal person, slow Ca2+ channels would control heart rate in which specific part of the heart?

SA node

In good health, what part of the body clears LDL (and HDL) from the blood stream?

liver

How does nitroglycerine help to relieve angina pectoris?

relax artery smooth muscle

What is the likely mechanism that antioxidants might prevent heart attacks?

oxidized LDL is bad

Why isn't an atrial beat needed for most of the venous return to go to the ventricles during diatole?

tricuspid and bicuspid valves are open

What does the endothelium line?

blood vessels

If you took statins, what substance would decreased?

cholesterol

How do gap junctions contribute to heart function?

get action potential from one cell to another

Since there is not much blood pressure left, what is needed to help blood flow along in veins?

valves

Taking blood pressure, you inflate the cuff to 180 mm Hg, then lower it. You hear nothing until the systolic pressure is reached. After the diastolic pressure is passed, you hear
nothing. Why do you get sounds only between systolic and diastolic pressures?

turbulent

What causes the second heart sound at the end of systole?

semilunars snap shut

How does aspirin help to prevent heart attacks?

inhibits platelet aggregation

Where does the vena cava (superior and inferior) empty into?

right atrium

At the moment the semilunar valves open, what is the blood pressure in the left ventricle?

same as arterial diastolic

What is the function of an arteriovenous anastomosis?

shunt blood from peripheral vascular bed

What is the endothelium?

cell lining of blood vessels

What is a heart murmur?

a leaky valve

Compare the duration of the isovolumetric portion of the ventricular contraction for someone with high diastolic blood pressure with that for a normal person.

the ventricle would contract further before forcing open the valves to arteries (for high b.p.)

What regulates the precapillary sphincter?

the sympathetic nervous system

"CN" in "HCN channels" stands for "cyclic nucleotide." What do cyclic nucleotides have to do with pacemaker cells?

adrenergic receptor affects cAMP level

Explain the interval between the QRT complex and the T wave in terms of the shape of the myocardial action potential.

that is a long action potential, QRS is depolarization, T is repolarization

How could you get a heart beat if there were no trigger from the SA node?

Eventually the AV node would kick in

At the moment of the last Korotkoff sound, what does the pressure dial show?

diastolic b.p.

What are baroreceptors in the carotid sinus used for?

regulate b.p.

In addition to increasing contractility, what does sympathetic input to the heart do?

regulate heart rate

What is ischemia?

interuption of blood flow and hence oxygen supply

What does a defibrillator do to save your life?

starts heart again, makes it so SA node triggers heart

What does a high HDL/LDL ratio in your blood test results imply?

less risk for coronary artery problems

As opposed to apoptosis, what is the damage to cardiomyocytes in a heart attack?

necrosis

What is it called when you have pain in parts of your body, like your left arm, in a heart attack?

referred pain

What is a thrombus and why is it potentially damaging?

a blood clot that clogs the artery

What event occurs at the end of the isovolumetric contraction of the left ventricle?

Aortic semilunar valve opens

Why do veins need to have valves to ensure forward blood flow while arteries do not?

there is no blood pressure driving the blood

In what way does the Frank-Starling law differ from the striated muscle's length-tension curve?

FS-More stretch (ventricular filling) more contraction, striated weaker when muscle is long

Why is the first part of the ventricular contraction isovolumic?

Bicuspid and tricuspid are closed, semilunars do not open until ventricular pressure > arterial

Heart cells die by cell damage, rather than by programmed cell death (apoptosis). What is the term used for this kind of damage?

necrosis

A blood test shows that a patient has a high HDL to LDL ratio. What does this mean?

these are good numbers re artery health

In an arteriole, what would a precapillary sphincter do under the influence of the autonomic nervous system?

open or close to regulate blood flow to the capillary bed

What valves close right at the start of ventricular contraction?

tricuspid and bicuspid (atrioventricular)

Hyperpolarization cyclic nucleotide (HCN) channels are important in pacemaker cells. Name the relevant and famous cyclic nucleotide, the one controlled by beta-1 adrenergic receptors.

cAMP

In atria, the action potentials are passed from one myocardial cell to the next. Why are there additional fibers (bundle of His, bundle branches, and Purkinje fibers) for ventricles?

to speed the action potentials to the base

Parasympathetic fibers slow the SA and AV nodes below their rate of automaticity. What nerve is this?

vagus, 10th cranial

Above the systolic pressure and below the diastolic pressure, you hear nothing. Why are there Korotkoff sounds between systolic and diastolic pressure?

blood flow is turbulent

What does the Wiggers diagram tell us about the opening of the aortic semilunar valve when the diastolic blood pressure is high?

ventricular pressure would have to be higher to push open the valve

Give an approximate value for the blood pressure in the ventricles during diastole.

zero

What symptom would be noticed if the heart muscle were to attempt anaerobic metabolism?

pain (angina)

What do aspirin, coumaden and the rat poison WARFarin have in common?

they inhibit coagulation

Valves between where and where snap shut at the beginning of ventricular contraction?

atria and ventricles

For part of the heart cycle, ventricular and arterial pressures are equal. How do these two pressures relate the rest of the time?

in diastole, ventricular is lower than arterial

What holds shut the aortic and pulmonary semilunar valves during the beginning of ventricular contraction?

arterial pressure

In addition to the automatic tissues (predominantly SA & AV nodes) to what does the sympathetic nervous system connect and why?

heart muscle to increase contractility

Electrically, what do pacemaker cells during diastole?

depolarize

How come the electrocardiogram can reach as far as the wrists and ankles for recording?

virtually no extracellular resistance

What would happen to the time between Q and T waves with sympathetic activation?

shorten

What is the difference between a thrombus and an embolism?

thrombus clot forms locally, embolism dislodged from elsewhere and arrives at trouble spot

Why would a large area of damage in the heart lead to re-entry of excitation?

the distance from cell to cell to cell would have the spike arriving after the refractory period is over

What type of cell is used for continuous and fenestrated capillaries?

endothelial

What is it that may shunt blood from arteriole to venule to bypass capillary bed in the skin?

arteriovenous anastomoses

In what way is heart muscle different from striated muscle with respect to strength as a function of length?

Frank Starling law has it that fuller (more stretched) ventricle has higher contractility, while striated muscle tension drops off

As cuff pressure is being released, between the systolic blood pressure and the diastolic pressure, your figure indicated that you get "sounds at every systole." Why?

turbulent blood flow

How would nitroglycerine help if you felt a heart attack coming on?

relax smooth muscle in artery

Describe referred pain as it refers to heart attack.

projected to neck, arms

What is it that makes the bicuspid and tricuspid valves close to make the first heart sound ("lub")?

pressure in the ventricles closes these atrio-ventricular valves

Why might a person pass out if (s)he stands without moving for a long time?

muscular contraction contributes to venous return, hence venous pooling

What part of the nervous system would regulate the precapillary sphincter?

sympathetic

During ventricular systole, just when the pressure forces the aortic semilunar valve open, what is the arterial blood pressure?

equal to the diastolic pressure right then

About what fraction of ventricular filling is from the beat of the atria?

a very small amount, the figure shows about 10 out of 80 ml

What happens to the brachial artery when the blood pressure cuff is first fully inflated?

it is completely closed

Suppose your SA node failed to fire. You would probably still have a heartbeat (how?) and it might be reasonably adequate (why?).

AV node would fire, see q 10, most of the ventricular filling does not rely on atria

What happens to the electrical potential of a cell in the sinoatrial (SA) node during diastole?

there is diastolic depolarization in these pacemaker cells until threshold is reached

How do we get recordings from 3 different "leads" in Eindhoven's triangle starting with a positive electrode connected to one wrist, a negative electrode connected to the other, and ground connected to an ankle?

The three so-called "leads" are gotten by swapping (2 at a time) connections to the 3 locations

Before paramedics arrive with the defibrillator, why is cardiopulmonary resuscitation essential?

CPR delivers enough oxygenated blood to the brain to keep it alive

"The bad news is that your cholesterol is high. The good news is that your ratio is good." What would be a good ratio (when the cholesterol level is broken down into its components)?

If HDL/LDL is high

At the peak of systole, how does the pressure in the right ventricle compare with the pressure in the left ventricle?

Way lower pressure in pulmonary circulation

Both branches of the autonomic nervous system (sympathetic and parasympathetic) connect to both nodes of the heart(SA and AV). In addition, the sympathetic nervous system also makes additional connections to the heart (to where? Or for what purpose?).

to muscle to increase strength of contraction

What would happen to the Q-T interval during strenuous exercise?

shorten

What is the function of an arteriovenous anastomosis?

Shunt blood to bypass capillaries in skin to prevent heat loss


this page was last updated 7/1/09

**The respiration lecture

RESPIRATION

Fox Chapter 16

"Plumbing"

TRANSPARENCY (review from introductory course)
Summarizes much of what will be said below, including the next transparency.
Nasal - moisture (smell) sniffing
Pharynx - larynx
Vocal cords larynx (laryngitis) "voice box"
Equal time to creationism : "Adam's apple"
Further down cilia sweep mucus, bacteria, dust up
(histology picture of cilia)
Cilia sweep from pharynx to esophagus (where you can swallow "crud")
Smoking paralyses ciliary sweep (more crud, less sweeping, famously asbestos is worse in smokers)

Fig. 16.4
Trachea - rings of cartilage to hold tube open like a vacuum cleaner hose
2 bronchi
Inflammation of the bronchi is called bronchitis.

Review chapter 9 material and note that sympathetic n.s. causes relaxation of smooth muscle (opening passageways) in lungs and parasympathetic n.s. constricts them (closing passageaways). The purpose is to regulate air flow.

Asthma caused by mast cells and eosinophils secreting leucotrienes, bronchioconstriction, use epinephrine to stimulate beta 2 receptors (note heart has beta 1 receptors). Epinephrine was in inhalers. Terbutaline is an anti beta 2 drug. Singulair is an antileukotriene. Because inspiration helps to open the bronchioles, breathing out (this is counterintuitive) is most difficult.

Alveoli 600 million in human 50 x skin area
Here is a picture from our histology course (like Fig. 16.18) showing how thin the cell layers of alveoli are.

Fig. 16.17
Emphysema - alveoli merge, often results from smoking, increased muscular effort in breathing- smoetimes they have a hunch back from using back to help breathe. These are the people older than they look pulling a dolly of oxygen around with them.

Fig. 16.20
[much like part of the figure from introductory course]
Air sacs (alveoli) are close to capillaries.
Note, red vs blue for arteriole vs venule is reversed for pulmonary circulation, obviously.
Recall, pressure lower in pulmonary circulation, and there is no regulation of flow to different areas as there is in systemic circulation.

Air Pressure

Fig. 16.18
Atmospheric pressure is measured in mm Hg

Fig. 16.19
Partial pressures of inspired air and alveolar air
Pressure relates to gas exchange.
In alveoli, H2O & CO2 higher and O2 lower for obvious reasons that we will chat about.

Fig. 16.22
Here is the cardio-respiratory system with blue blood (P O2=40, P CO2=46) and red blood (P O2=100, P CO2 = 40)

Lung volumes

Fig. 16.15 also here
Breathing in and out normally is called tidal breathing, volume about half a liter. There is an expiratory reserve, over a liter, and an inspiratory reserve, maybe 3 l. From the top of inspiration to the bottom of expiration is vital capacity. Even after you empty your lungs as much as possible there is a residual volume, over one liter.

A simple spirometer with a dispo tube to breathe into can be used cheaply to measure vital capacity, tidal volume and expiratory reserve.

A summary point: not all the air exchanges!

Ventillation

Fig. 16.7
Pleura, very slippery, and pleural cavity, slightly lower than atmospheric pressure, are important.
Pleurisy is inflammation of pleura, breathing is painful.
The low pleural pressure keeps the lungs open unless an injury lets air into cavity, "pneumothorax," collapses lung.

Fig. 16.14
Inspiration - pressure in lungs is lower than atmospheric, obviously, a word I seem to be using often, and expiration, pressure is higher.

Fig. 16.13
Muscles involved: intercostals and diaphragm mostly, and others as well.
Subtle differences for inspiration and expiration.

Fig. 16.11
Water's surface tension would tend to collapse (close) alveoli. Type II alveolar cells secrete surfactant (surface active agent), phosphatidylcholine plus phosphatidylglycerol, that decreases surface tension. RDS (respiratory distress syndrome) aflicts premature babies since surfactant production does not start until late.

Cystic fibrosis is from mutation in CFTR (cystic fibrosis transmembrane regulator), a chloride channel, results in viscous mucus.

Control of ventillation

Introduction: The receptors that are sensitive to changes in the concentrations of CO2 and H+ are located within the arterial system and the medulla of the brain. Excitation of these receptors trigger neural reflexes which alter the respiratory rate and depth. Additionally, other parts of the nervous system influence the basic ventilation pattern established by the respiratory center.

Fig. 16.24
Medulla rhythmicity center generates rhythm
Input from Pontine apneustic center (inspiration). Have you heard of sleep apnea?
Input from pontine pneumotaxic center counteracts inspiration.

Fig. 16.25
There are chemoreceptors in the aortic and carotid bodies, go to medulla in vagus (X) and glossopharyngeal (IX) respectively.

Fig. 16.26
This diagram adds a few items:
(1) Cerebral cortex over-rides. The funny thing about this information is that it is hard for you to think about how you breathe without you changinging how you breathe.
(2) There are important chemoreceptors in the medulla.

Fig. 16.28
Without the buffers that blood has, cerebrospinal fluid (CSF) on the other side of the blood brain barrier has CO2 and H2O -> carbonic acid generating H+ that affects receptors.

Summary. A common misconception is that variation in the O2 levels within the system cause changes in the ventilation rate. Actually, the O2 concentration, under normal conditions, has little to do with the determination of respiratory rate. The critical determining factor is the level of CO2 and/or the level of free protons circulating in the blood. For example, an increase in CO2 or H+ levels will induce changes which result in an acceleration of the ventilation rate and volume until these levels return to the normal range. Conversely, conditions associated with alkalosis and lower than normal CO2 levels depress the ventilation rate.

CO2 and CSF acidity are stimuli for breathing, and that is why oxygen given to patients has CO2 in it.

Fig. 16.28
Decreased breathing increases CO2 etc., resulting in a compensatory (there's that old negative feedback again) increase in breathing.

Fig. 16.27
Hyperventillation - blow off CO2 and desire to breathe less, can hold breath.

Transport of O2 and CO2

Fig. 16.31
The trouble is that oxygen does not dissolve well in water, 66 x as much oxygen is in blood, with its hemoglobin, than in plasma.

Fig. 16.32
Everyone should know that hemoglobin is composed of 2 alpha chains, 2 beta chains, and heme with iron in it.

Fig. 16.33
Here is the famous oxyhemoglobin dissociation curve, % oxyhemoglobin saturation as a function of P O2 (mmHg).
By comparing arteries with veins, we can see how much oxygen is offloaded to tissues.

Fig. 16.37
Importantly, hemoglobin will offload oxygen to myoglobin based on the displacement.

(The same is true for the relation of adult hemoglobin and fetal hemoglobin.)

Fig. 16.38
From tissue to blood:
CO2 transported as bicarbonate, bound to hemoglobin, and dissolved in blood
CO2 dissolves better than O2 in water
Red blood cells CO2 + H2) -> (carbonic anhydrase)-> H2CO3 (carbonic acid).
then H2CO3 -> H+ and HCO3- (bicarbonate)
When this diffuses out of RBC, Cl- goes in (chloride shift)

Fig. 16.39
The reverse happens to put CO2 from blood to alveoli.

Exam questions from 2004 - 2008 relating to this outline

If you hyperventillated, what would become of the pH of the cerebrospinal fluid?

less CO2, pH goes up

What is the biological word for the Adam's apple?

larynx

Expiratory reserve plus inspiratory reserve plus tidal volume equals what?

vital capacity

What is the chloride shift?

Cl- goes into erythrocyte when HCO3- comes out and vice versa

What is the intrapleural pressure? (I want an approximate value.)

slightly less than atmospheric

What two gasses have much higher partial pressure in alveolar air than in inspired air?

H2O, CO2

What are the pneumotaxic center and the apneustic center used to control?

respiratory rhythm

Cystic fibrosis is a channel for what ion?

Cl-

An asthma spray would contain an agonist for what naturally ocurring neurotransmitter?

norepinephrine

Where are the brain centers that control breathing?

medulla and pons area

The abscissa (X-axis) of the oxyhemoglobin dissociation curve is partial pressure of O2 in mm Hg. What is plotted on the ordinate (Y-axis)?

% saturation (with O2) of hemoglobin

What compound (related to but not the same as prostaglandins) constricts bronchial smooth muscle (blocked by Singulair)?

leukotriene

One reason that the partial pressure of CO2 is higher in alveoli than in the atmosphere is that cells generate CO2 (as waste). What is the other reason?

not all the air in the lungs is exchanged by breathing

Partial pressures for CO2 and O2 are almost equal in alveolar air and pulmonary veins. For which gas is there a greater difference between alveolar air and pulmonary arteries?

O2

Which component of lung volume cannot be measured with a spirometer?

residual volume

What is the naturally ocurring hormone for beta-2 receptors in bronchi?

epinephrine

What is the highest level that mercury would rise in a glass tube with a vacuum at the top?

760 mm

Respiratory distress syndrome in premature infants results from the lack of what molecule?

surfactant (phosphatidyl choline)

Where do chemoreceptors in aortic and carotid bodies feed to to control breathing?

medulla

What would alkaline cerebrospinal fluid do to breathing?

inhibit it

In pneumothorax, what compartment increases its pressure to that of the atmosphere?

intrapleural

In addition to containing heme, how would you describe the molecular structure of hemoglobin?

2 alpha and 2 beta protein chains

A figure in your text indicated that one place was responsible for "automatic breathing," while I cautioned you that this was very different from automaticity in the heart. What is this place that generates automatic breathing?

Medulla

Bicarbonate in plasma helps in CO2 transport. It is made with the help of what enzyme in what cell?

carbonic anhydrase in red blood cell

What would O2 on mother's hemoglobin do when it gets near fetus hemoglobin in the placenta?

offload to fetal

When is the pressure in the alveoli slightly higher than atmospheric?

expiration

The total lung capacity is tidal volume + inspiratory reserve + expiratory reserve + what?

residual volume

What is the significance of the value 760 mm Hg?

atmospheric pressure at sea level

Why does a mutant chloride (Cl-) channel (CFTR specifically) lead to lung disease?

poor ion transport -> poor water transpord -> viscous mucous

For the sake of CO2 transport, where is bicarbonate (HCO3-) made and where is it carried?

made in RBC, carried in plasma

Why is the partial pressure for alveolar H2O much higher than for H2O in inspired air?

air is humidified, usually in nasal passageways

What common effect (though to different extents) do leukotrienes and the parasympathetic nervous system have on bronchioles?

decrease air flow

What does emphysema do to the number of alveoli?

decrease since adjacent ones merge

Why is the partial pressure for CO2 higher in the pulmonary artery than in the alveoli?

pulmonary artery carries CO2 offloaded by tissue respiration

Although phosphatidylcholine is best known as a membrane phospholipids, it also has a special function in the lungs. What is this function.

component of surfactant, decrease surface tension of water

You breathe in and out your vital capacity a dozen times in rapid succession. What is this called and why would your urge to breathe be decreased for the next minute?

hyperventillation, by blowing off CO2, less H+ in medulla

A stab wound to the chest can lead to the collapse of a lung because what compartment would increase its pressure to atmospheric pressure?

intrapleural space

What is the important nerve connecting the heart and the brain that carries chemoreceptive signals from the aortic bodies?

vagus (10th cranial)

Why would you want to inhale adrenalin? (Your answer can address pathology, cells or molecules.)

asthma, relax smooth muscle, open bronchial airways, activate beta 2 adrenergic receptors

Why is the partial pressure of oxygen lower in alveoli lower than in the outside air?

because water vapor and carbon dioxide fractions are so much higher

A slight increase in pressure (where?) would allow the lung to collapse if there were a stab wound to the chest?

intrapleural space

Why would asbestos be more likely to stay in the lungs of smokers than of non-smokers?

smoking paralyses cilia

How does intrapleural pressure relate to alveolar pressure (at rest, breathing in and breathing out)?

a little lower in all cases

Why would it take more effort than a premature baby could muster to breathe?

there is no surfactant to decrease water tension

Name one of the two nerves that carry chemosensory input to the brain to control respiration?

glossopharyngial (9th) and vagus (10th)

Why is it so useful to monitor pH of the cerebrospinal fluid to report the need to breathe?

carbon dioxide would make pH go down

What does the sympathetic nervous system do in bronchi? (Your answer can either be at the level of the cellular response or of the passageway function.)

beta 2 receptors relax smooth muscle open airway

What could you do to lower the partial pressure of carbon dioxide in your alveoli?

hyperventillate

Give a ballpark figure for the partial pressure of carbon dioxide in the arteries for normal breathing and for hyperventilation.

40 mm Hg, less if hyperventillate

Why does chloride need to go in and out of red blood cells?

to move bicarbonate to plasma where there is room to carry it

Why wouldn't you expect inhibitors of prostaglandin synthesis to help with inflammation in asthma?

Leukotrienes, not prostaglandins

Total lung capacity minus expiratory reserve minus inspiratory reserve minus residual volume equals what?

Tidal volume

What happens to the pressure in what compartment to cause the lung to collapse?

Intrapleural becomes equal to atmospheric

Other than the medulla (of the brain), where are there chemoreceptors to control ventilation? (or, if you prefer, tell me how they feed to the brain.)

aortic and carotid bodies

What is the purpose of cilia in the trachea?

to sweep gunk captured in mucus up to where it gets swallowed

How would epinephrine in an inhaler affect breathing? (Your answer could apply to molecular type of the receptor or to affect on the airway.)

beta 2, dilate (open) bronchioles

What is it that would make mercury go up 760 mm in a glass tube?

atmospheric pressure (not "suction")

Give at least 2 reasons oxygen's partial pressure is so much lower in alveoli than in the atmosphere.

our of 3: (1) there is so much CO2 in alveoli, (2) there is so much H2O in alveopi, (3) not all air is exchanged each breath

The partial pressure for carbon dioxide in the pulmonary artery is 46. What is it in the pulmonary vein?

lower, but not that much lower (40)

Why would they put premature babies in high oxygen?

lack of surfactant makes breathing difficult

Relative to carbon dioxide, how much oxygen is carried in the plasma?

O2 is way less soluable in water than CO2 (the figure clearly showed 10% for CO2, another figure implied about 1.5 % for O2)

"Most bicarbonate is carried in the plasma." But it was made in the erythrocyte. What trickery was used to move it to the plasma?

exchange with Cl-



this page was last revised 7/9/09

**The kidney lecture

Excretion and homeostasis

Fox Chapter 17, one figure from Chapter 6

How the kidneys function is way more interesting than you may have thought. Summarizing, they throw the baby out with the bath water, then recover most of it.

Consider the work of the kidneys

Artificial kidney (dialysis) 10 hr 2 times per week
This is why transplant important, and there is difficulty getting a compatable donor.
Cell makes wastes that go into the plasma.
Heart pumps 7000 l/day (32 55 gal drums).
1/4 (8 55 gal drums) through kidneys
Glomerulus - Bowman's capsule passes (filters) 180 l/day.
And yet only 1 l of urine is produced per day.

Osmoregulation (for ions)

Review:
Hypertonic (concentrated), isotonic, hypotonic (dilute).
Nitrogenous waste (urea) is from catabolism of amino acids and nucleotides.
Ammonia (toxic) would be o.k. for small water animals where it can diffuse away.

Comparative biology

There is a tradition in undergraduate biology to emphasize comparative aspects:
Malpighian tubule in insects puts out uric acid and rectum recovers water and other molecules.
Uric acid is used in birds, reptiles, and insects, and water loss is minimized

The nitrogen story

Although 78% of the atmosphere is nitrogen in the form of N2, this is fairly unreactive.
Thus there are these important processes: N2 to NH3 nitrogen fixation, NH3 to NO3- (nitrate) nitrification, NO3 to NH3 (nitrate reduction) in plant roots.
Also nitrogen is recycled.
In Pacific, off the coast of Peru, the Humbolt current causes an upwelling of nutrients, anchovies thrive, bird droppings (guano) were used as fertilizer.
El Nino (the Child, named not for misbehavior but because it comes near Christmas) is a periodic climate misbehavior that disrupts this.

The uric acid story

In humans, mild accumulation of uric acid causes gout - crystals in joint cause inflammatory response which is treated by NSAIDS (non-steroidal anti-inflammatory drugs like prostaglandin inhibitors like indomethacin, ibuprophin, and aspirin). Enzyme is inhibited by chronic treatment with allopurinol. Genetically pathological uric acid accumulation which is Lesch-Nyhan syndome - children have bizarre self mutilation from HGPRTase (hypoxanthine guanine phospho ribosyl transferase) deficiency.

Functional anatomy

Fig. 17.1
kidney, ureter, bladder, urethra

Fig. 17.2
Kidney
Pelvis=basin; Medulla=marrow; Cortex=bark ("medulla" and "cortex" are terms used a lot, like in brain and in adrenal gland)
The blood supply is huge (1/4-15 of body at rest) and regulated (way less in stress)
Renal artery and vein branches near eachother
each kidney has 1 million nephrons:
Capsule, PCT, loop of Henle, DCT, collecting duct (this will be repeated in other figures)

Filtration

Fig. 17.5
Blood flow in glomeruli
Notice "afferent" (toward) and "efferent" (away from) arterioles, implies a portal system to next capillary bed iaround nephron and in medulla

Fig. 17.13
Glomerulus - Bowman's (glomerular) capsule
I picked just one figure, when the book uses several to develop the point gradually.
Blood pressure and osmotic pressure drives sieve
Green is protein that is too big to fit through.
Blue is all small molecules.
Na+ is actively transported, Cl- and H2O follow

Fig. 17.7
Fig. 17.9
Glomerulus - fenestrae (windows) in capillaries and slits between podocyte pedicels make up sieve.
here is a picture from the histology course
another picture highlights glomerulus by dye injected into artery
large molecules dye do not pass
- small molecules dye passes through
blood proteins and cells do not pass
urinalysis strips test if blood, cells or protein is present

Clearance test for filtration

Fig. 17.22
One test of kidney function, specifically filtration, is inulin clearance test
Inulin is an injected dye that is filtered but not resorbed.
Short of injecting inulin, an endogenous molecule, creatinine, can be assayed.

Resorption of glucose

Fig. 17.24
Proximal Convvoluted tubule - bring back amino acids, glucose note active (NaCl) vs passive (water) transport
Glucose is a special case.
(1) ATP is used in a Na+-K+ pump on basolateral cell surface
(2) glucose is cotransported with Na+ on apical cell surface
(3) Cells are joined so there are no other pathways
(4) recovery in capillary is by diffusion
Why an untreated diabetic has glucose in the urine is that this mechanism is saturated and cannot recover all of the glucose filtered from high blood glucose.

Resorption of salt

Kangaroo rat - metabolic water, hypertonic urine

Fig. 17.15
Ascending loop - salt resorbed but not water
Ascending loop of Henle - salt outward resorption is stimulated by aldosterone
Some passive water recovery is made possible because of high tonicity of interstitial fluid in the medulla.
This is called the countercurrant system

Fig. 17.18
A summary shows dilute in cortex, hypertonic in medulla

Secretion

Fig. 17.21
Kidney also secretes - pump out (penicillin)

Hormonal control

TRANSPARENCY (from an intro book)
ADH (vasopressin) makes water follow back into interstitial fluid which is hypertonic from salt
alcohol and caffeine inhibit ADH, hence diuresis (excessive urination)
affects water channels called aquaporins

Fig. 17.20
regulation of ADH by negative feedback (from hypothalamus to pituitary) and relation to thirst and water intake

Fig. 6.14
This same concept was covered way back in Chapter 6.
The relation of thirst to water conservation via ADH

Fig. 17.26
low blood pressure -> JGA (juxtaglomerular apparatus) makes renin

Fig. 17.27
Renin causes Angiotensinogen (liver) -> angiotensin II- closes arterioles
stimulates aldosterone

High blood pressure ->atrial natriuretic protein ->(-) aldosterone and renin

Sweat

Filter, resorb (salt and water)
Sweat pores not as good -which is why gatorade tastes good to athletes
especially bad in cystic fibrosis (salty sweat) molecular genetics shows a chloride channel defect

Exam questions from 2004 - 2008 relating to this outline

Blood arrives at the glomerulus for filtration. What do they call the blood vessel that carries blood away from the glomerulus?

efferent arteriole

In addition to facilitated diffusion at the basolateral cell surface, what is necessary for glucose transport in kidney tubule and intestinal cell? (Include process and location.)

apical cotransport with Na+

What is the product of the juxtaglomerular apparatus?

renin

High levels of what nitrogen-containing chemical cause gout?

uric acid

Why are alcoholic beverages contraindicated to stay hydrated in times of heat stress? (Make sure your answer says what happens to the relevant hormone level.)

alcohol inhibits ADH, more water is lost through kidney

Cystic fibrosis is a channel for what ion?

Cl-

Where are the cell bodies of the cells whose axon terminals release ADH and oxytocin?

hypothalamus

What does creatinine clearance test for?

glomerular filtration

In the intestine and the kidney tubule, three processes are needed for glucose transport, (1) basolateral sodium pump, (2) basolateral facilitated diffusion, and (3) apical... [your
turn].

glucose/sodium cotransporter

Because of the portal system, the vessel carrying blood from the glomerulus is not called a vein. What is it called instead?

efferent arteriole

If a kidney stone passed from the kidney to the bladder, what tube would it go through?

ureter

What accumulates in Lesch-Nyhan syndrome?

uric acid

By what mechanism are proteins excluded from the primary filtrate in the kidney?

size of sieve openings (podocytes and fenestrated endothelium

Why might you give a secretion blocker in conjunction with penicilin?

keep antibiotic from being pumped out by kidney

Why do cells in the proximal convoluted tubule need to pump sodium to reclaim glucose?

because of sodium-glucose cotransporter ion apical surface

In what tube does the final, ADH-dependent, water reclamation occur?

collecting duct

Instead of injecting inulin, what test is there for clearance assaying for a substance already in the body?

creatinine

Renin activates what hormone?

angiotensin II

In the kidney tubules, salt and water are reclaimed. Only one substance is actively transported. What substance? (Be specific.)

sodium

What hormone from the adrenal cortex is essential for salvaging salt in the kidney?

aldosterone

There is a capillary bed in the glomerulus. Where is the other capillary bed of this portal system?

medulla

Na+, Cl- and H2O are all recovered in the proximal convoluted tubule. Which involve active transport?

Na+

Aquaporins in the collecting ducts are regulated hormonally. What are aquaporins?

ater channels

At what location in the lumen of the kidney tubules is the tonicity the highest?

loop of Henle (and maybe deep collecting duct)

Describe either how the kidney deals with inulin or, alternatively, what specific aspect of kidney function inulin is used to test.

filters but does not retrieve, tests GFR=glomerular filtration rate

Considering how unreactive nitrogen gas (N2) is, how did it get into biological molecules such as amino acids?

nitrogen fixation

The glomeruli vs. the loops of Henle are in which two overall anatomical portions of the kidney respectively?

cortex, medulla

In addition to the fenestrations in capillaries, what cellular architecture is responsible for glomerular filtration?

pedicels of podocytes

What change in appetite would occur if the adrenal glands were removed?

you would crave salt

What is detected by the juxtaglomerular apparatus that makes these granular cells release their renin?

pressure in afferent arteriole

If you drink very little and become thirsty, what pituitary hormone would be increased?

ADH=antidiuretic hormone

What are creatinine and inulin reapectively and what are they used for?

creatinine is already in body and inulin is injected, buth used to test glomerular filtration since they are filtered but not resorbed

For glucose in the kidney, tell me the surface locations of the three transporters involved.

cotransport apical, basolateral facilitated diffusion plus sodium pump

What should happen to the tonicity of urine if a drug that inhibits ADH (antidiuretic hormone) were administered?

becomes dilute

Why are drugs like aspirin called prostaglandin inhibitors?

they block synthesis by blocking the cyclooxygenase (COX)

What is the tube that connects the kidney with the bladder?

ureter

What do they call the blood vessel exiting the capillary bed that is in the glomerulus?

efferent arteriole

Salt and water are recovered in the proximal convoluted tubule. What is active and what is passive? Be specific.

sodium ion active, chloride and water passive

Why would a rat drink salty water after an adrenalectomy?

aldosterone which favors salt recovery would be missing

Where, in the nephron's components, are the aquaporins that are influenced by ADH (antidiuretic hormone)?

collecting ducts

What does the juxtaglomerular apparatus monitor and why is it in a good location to do this job?

blood pressure, near afferent arteriole

From the renal pelvis, the urine flows to the bladder via what tube?

ureter

Why is it advantageous to have hypertonic interstitial fluid in the kidney medulla?

Then, if ADH is present, water will be salvaged from the collecting duct

Why would it be advantageous to position renin secreting cells where they are?

Blood pressure is monitored near the glomerulus for the emergency work of angiotensin that rennin initiates

Drugs that inhibit prostaglandin synthesis might help with the symptoms of gout. Why?

b/c it is the inflammatory response to the uric acid in the joint that is pain

What is wrong in Lesch-Nyhan syndrome children (HGPRTase deficiency)? (Your answer can be behavioral or chemical.)

self-mutilation, uric acid accumulation

What blood vessel connects the two capillary beds of the nephron and hence serves as the portal vessel?

the "arteriole" that is efferent from the glomerulus

Out of all the things a nephron does, inulin clearance tests for just one. What?

glomerular filtration

How is glucose transported at the apical surface of the cell of the kidney tubule?

apical is the co-transport with Na+

What would an adrenalectomy do a rat's specific appetites?

without aldosterone, there would be increased sodium appetite

What would inhibiting ADH do to the urine?

inhibiting antidiuresis, two negatives make a positive, so diuresis, more (and more dilute) urine



this page was last updated 7/15/09

**The digestion lecture

Digestion

Fox Chapter 18, figures from chapters 4, 6 & 19

Chemistry

TRANSPARENCY (From intro bio)
Fig. 18.1
break down long chain proteins, polysaccharides and nucleic acids into monomers
recall hydrolysis (opposite of dehydration synthesis) (hydro-water lysis-break apart)
if not broken down, proteins which are non-self would make a big antigen invasion

TRANSPARENCY (From intro book)
Tube - Alimentary canal

Input - output

Fig. 18.2
One emphasis will be on how the human digestive system invests many juices (hydrolases = enzymes which catalyse hydrolysis)
Some glands have ducts and these are called exocrine glands.
This is in contrast with endocrine glands (ductless, for hormones, which are also involved in digestion)

800 g food IN per day
1200 ml water
/
/ 7000 ml GLANDS
/
50 g solid OUT
100 g water

Overall anatomy

(from mouth to stomach)

Mouth - teeth, lubrication, salivary amylase to disaccharide maltose - starch tastes sweet (only starch in mouth)
-ase enzymes
Pharynx swallowing
Esophagus - bolus, peristalsis
Cardiac oriface

An integrative story

Rats cannot vomit (cardiac oriface cannot open for reverse peristalsis). They are very good at learning, in one trial, to permanently avoid tastes which make them sick. (You too may have developed a temporary dislike of foods you ate before getting sick.) They can only be poisoned by chemicals with a delayed reaction like Warfarin (warf = Wisconsin alumni research foundation) which is an anticoagulant. (It is also used in lower doses to prevent heart attack (coronary thrombosis).

Stomach

Fig. 18.5
Stomach - gastric mucosa - mucus protect

Fig. 18.6
from parietal cell: HCl kill bacteria
stop amylase
From chief cell: pepsinogen ---(HCl, pepsin))--> pepsin (proteolytic)
optimum pH for pepsin is 2
(Inactive forms called zymogens)
Heartburn, antacids, ulcer (although it is now known that a specific bacterium, Helicobacter pylori, is associated with ulcer)
very little absorption in stomach - exceptions: aspirin, alcohol

Fig. 4.4
The optimum pH for pepsin (proteolytic enzyme in stomach) is acidic while for trypsin (proteolytic enzyme in intestine) is slightly basic. And for salivary amylase, it is neutral.

Fig. 18.5 again
Pyloric sphincter regulates emptying of acidic gastric juice to duodenum.
In duodenum, bile from liver and bicarbonate and enzymes from pancreas add to enzymes from small intestine

Intestine:

enzymes - lactase, maltase, sucrase, others
mitosis - since cells digest themselves
absorption - food and water

Fig. 18.10
Villi (big) increase surface area. Note mitoses in crypts.

Here is a micrograph from our histology course dramatizing the tremendous increase in apical surface area of intestinal cells caused by the microvillar brush border.

Signalling by G-protein involving cAMP (covered earlier) is disrupted by cholera toxin - a life-threatening diarrhea, must replace fluids - salts and glucose (as in the electrolyte coctails athletes drink like Gatorade) facilitate water absorption

Fig. 18.12
The microvilli in the intestines have a special name, the brush border.
Protease (enteropeptidase turns trypsinogen into trypsin which, in turn, makes chymotrypsin and carboxypeptidase (and others)

Fig. 18.33
How proteins are broken down and absorbed is complex.
Trypsin and chymotrypsin are endopeptidases.
Carboxypeptidase, exopeptidase, cuts carboxy terminal.
Aminopeptidase (shown on brush border) cuts amino terminal.
Di- and tri-peptidases are intracellular.
Intestinal cells digest themselves, and their enzymes go into intestinal lumen.

Fig. 6.21
how glucose gets absorbed
same story as for kidney, and, in fact, notice "lumen of kidney tubule or small intestine"
apical, cotransport with sodium
basolateral Na+-K+ATPase plus glucose facilitated transport

Pancreas

Fig. 18.27b
Pancreas is responsible for dumping in many of the enzymes
Unit of this exocrine gland is the acinus
Zymogen refers to precursor of enzyme.

Table 18.4
"pro..." as in "procarboxypeptidase and "...ogen" as in "chymotrypsinogen" --a peptide fragment is cut off from a larger precursor protein to make active enzyme; there are many examples like this in biology, for instance prohormones cleaved to make active peptide hormones.
Pancreas puts out bicarbonate (alkaline) to neutralize stomach acid.
Optimum pH for for trypsin is 8.

Fig. 18.25
Pancreas and common bile duct (from liver and gall bladder) dumping into duodenum.
When I took organic chemistry lab (1966-7) we used gall stones for a cholesterol extraction.
Note: Islets of Langerhans (endocrine tissue) in pancreas where alpha cells make glucagon and beta cells make insulin.

Liver

Very few enzymes.
Emulsify fats.
Iron recycling.
Eliminate some wastes to feces.
Detoxify.

Detoxification

Portal blood veins (circulatory system "wired" in series is unusual, another famous example being the hypothalamus of the brain which feeds to the pituitary gland and kidney cortex to medulla). Via hepatic portal vein pick-up from small intestine is first delivered to liver cels. There, "microsomal fraction" (how biochemists view the smooth endoplasmic reticulum) has enzymes to detoxify. Enzymes like those that detoxify drugs like barbiturates are increased on exposure to toxins (inducible). Alcohol -(alcohol dehydrogenase (ADH) )-> aldehyde - (aldehyde dehydrogenase)-> acetic acid. With AcetylCoA, acetic acid can add to fatty acid chains 2 carbons at a time. There is a fatty metamorphosis of the liver from one binge. Continued heavy drinking leads to scarring and cirrhosis.

Fig. 18.22
Fig. 18.23
Erythrocyte iron recycling, bile pigment (bilirubin) ->urobilinogen turns feces dark.
Also colors urine.
Hepatitis (disorder which spills bile into blood) - turns skin yellow (jaundice) (feces are not as dark, urine is darker)

Fat digestion

Fig. 18.24
bile salts, salts of cholesterol, that emulsify fats

Fig. 18.35
Liver contributes to fat digestion

Fig. 18.34
Triglycerides are broken to monoglycerides and free fatty acids.

Fig. 18.36
Despite this breakdown, fats are reassembled, put in droplets with proteins and carried in lymph duct called lacteal.

Hormones

Table 18.5
Local hormones control digestion - Many found later in other places

Fig. 18.30
from stomach:
food stimulates gastrin which, in turn, stimulates gastric juice until there is a low (acidic) pH
from duodenum:
Cholecystokinin (CCK) - liver and pancreas
Secretin for bicarbonate release
Enterogastrones to slow gastric emptying

Appetite

It is worth mentioning that hunger and satiety are complex
In old work on brain lesions, LH (lateral hypothalamus) was called the hunger center, while the VMH (ventromedial hypothalamus) was considered to be the satiety center, but it never turned out to be so simple.
Hypothalamus is important in many motivated behaviors including thirst and sex drive.
Affect (the aspect of perception of goodness or badness of a stimulus) is linked through the nigrostriatal tract (bundle of nerve axons) which uses the neurotransmitter dopamine and which is deficient in patients who have Parkinson's disease.

Fig. 19.3
Now it appears that there is a hormone which is called leptin which is released by (well-fed) fat cells which causes the brain to decrease apetite.
Specific appetite for salt after adrenalectomy eliminates aldosterone.

Recent literature

Leptin

JKElmquist & JSFlier, The fat-brain axis enters a new dimension Science 304, 63-64, 2004 (Perspectives)

SGBouret, SJDraper & RBSimerly, Trophic action of Leptin on hypothalamic neurons that regulate feeding, Sci 304, 2004, 108-110

SPinto, AGRoseberry, HLiu, SDiano, MShanabrough, XCai, JMFriedman, TLHorvath, Rapid rewiring of arcuate nucleus feeding circuits by leptin, Sci 304, 2004, 110-115.

ob/ob mice are leptin deficient
arcuate nucleus of hypothalamus
orexigenic, Neuropeptide Y (NPY) and agouti-related protein (AgRP)
anorexigenic, proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART)
leptin regulates synaptic plasticity and axon guidance

Exam questions from 2004 - 2008 related to this outline

Loss of what hormone would cause an adrenalectomized animal to crave salt?

aldosterone

What is the function of the "microsomal fraction" in liver cells?

detoxify

Mitosis in the crypt of the villus is needed because of a short life expectancy of which cells?

intestinal epithelial cells

Repeated fatty metamorphosis of liver from alcohol binges leads to what scarring disorder?

cirrhosis

In addition to facilitated diffusion at the basolateral cell surface, what is necessary for glucose transport in kidney tubule and intestinal cell? (Include process and location.)

apical cotransport with Na+

What hormone from adipose tissue contributes to weight regulation?

leptin

The opposite of dehydration synthesis (condensation reaction) happens in digestion. What is this called?

hydrolysis

What is the optimum pH for pepsin?

very acidic (2)

Recycling of what kind of cell contributes to the dark color of feces, the yellow color of urine and the yellow skin in jaundice?

red blood cells

What is a zymogen?

inactive forms of digestive enzymes

Where does trypsinogen come from?

pancreas

Cholera toxin affects the level of what famous "second messenger" in the intestinal epithelium?

cAMP

The portal vessel in the digestive system connects the intestine (where absorption takes place) to that organ?

liver (its the hepatic portal vessel)

Jaundice is a symptom of a disorder of what organ?

liver

What is the function of cholecystokinin (CCK)?

hormone in digestion, slows gastric emptying, cranks up pancreatic secretions

What is the function of salts of cholesterol made by the liver and secreted into the small intestine?

emulsify fats

In the intestine and the kidney tubule, three processes are needed for glucose transport, (1) basolateral sodium pump, (2) basolateral facilitated diffusion, and (3) apical... [your
turn].

glucose/sodium cotransporter

Cholera toxin interferes with water transport in the intestines in a mechanism utilizing what famous "second messenger?"

cAMP

What is the name of the lymph vessel in the intestinal villus that is important if absorption of fat?

lacteal

Many factors including hormones control gastric emptying via what "valve?"

pyloric sphincter

When I was in first grade, we were told to keep a saltine cracker in our mouth and notice that eventually it tasted sweet. What enzyme is responsible for this?

amylase

You swallow a bolus, and it gets broken apart and mixed with lots of fluid. What is the name of the fluid mixture emptying into the intestine?

chyme

What do you call the inclusions in pancreatic acinar cells with reference to the fact that they contain precursors of enzymes?

zymogen granules

What is the name biochemists use for the smooth endoplasmic reticulum of liver cells responsible for detoxifying toxins?

microsomal fraction

Where are the dipeptidases and tripeptidases responsible for the final breakdown of proteins to amino acids in digestion?

inside the intestinal cell

If one glucose transporter is on the brush border, where (specific cell surface) is the other?

basolateral

In a healthy person, what is the fate of bilirubin after it arrives at the liver?

converted and out in feces

What is the source of the digestive enzyme that converts fats to fatty acids plus a monoglyceride?

lipase is from pancreas

What does it mean to say a substance is orexigenic?

makes you want to eat

Where is the median eminence?

Where hypothalamus connects to pituitary

Argue that the effect of a hypothalamic lesion on weight regulation might result from loss of affect by interrupting the nigrostriatal tract. Be specific about what effect you are talking about and/or what part of the hypothalamus.

weight loss from lateral hypothalamus lesion might be from not appreciatng the "goodness" of food

List one (of the several) effect of gastrin.

make parietal cell secrete HCl or chief cell secrete pepsinogen (or ECL cell secrete histamine)

Why is a portion of the hypothalamus referred to as "supraoptic?"

it is above optic chiasm

In what molecular form is fat absorbed from the intestinal cell (to the body)?

triglycerides combined with protein in droplet called chylomicron

Name an enzyme derived from a pancreatic precursor that is an endopeptidase.

trypsin, chymotrypsin

What are zymogen granules in pancreatic acinar cells?

contain precursors of digestive enzymes like trypsinogen

"Enterokinase on the brush border cleaves trypsinogen to activate trypsin." Translate.

the microvilli on intestinal epithelial cells activate the proteolytic enzyme by cutting off a peptide fragment

What is the purpose of bicarbonate secretion by the pancreas?

neutralize stomach acid for intestine

"Proteins are hydrolyzed into singal amino acids to be absorbed by intestinal epithelial cells and passed into the blood stream." Why is this not the whole truth?

peptides of 2 and 3 aminoacids can be taken into cell for final breakdown in cell

As heme is broken down, one of the products is bilirubin. What becomes of this substance?

conjugated to gluconuride, converted to uropilinogen, put out in feces and urine

The hepatic portal vein carries blood from the small intestine to where?

liver

What happens to a monoglyceride inside a cell of the small intestine?

two fatty acids added (converted to fat (triglyceride)

Gastrin stimulates secretions of parietal and chief cells. Name these secrtetions.

HCl, pepsinogen

What would be the cause of death if you had cholera, and how might you prevent death if you were nowhere near medical help?

dehydration, gatorade

What specialization in the stomach regulates gastric emptying into the small intestine?

pyloric sphincter

"Leptin causes a decrease of the orexigenic neuropeptide Y from the arcuate nucleus." Translate.

neuropeptide Y from that part of the hypothalamus would cause the opposite of anorexia, so the protein leptin should be good for weight loss

Go on a drinking binge and there will be fat in the liver the next day. Biochemically, how did that fat get there?

alcohol -> aldehyde -> acetic acid (adds 2 carbons to a fatty acid)

The same sort of drug given to heart patients to decrease the likeliness of a thrombus is very useful as a rat or mouse poison. Why?

rats avoid tastes of foods that made them sick and anticoagulants work so slowly that they never make the association

Bilirubin results from what ativity in what organ?

derived from red blood cell hemoglobin, handled by liver

What molecules make up the chylomicrons that are transported to the lacteal?

triglycerides plus proteins

Why are ob/ob mice obese?

lack leptin

What is the word for the coordinated wave of smooth muscle contraction that propels a bolus of food forward through the esophagus?

peristalsis

Baking soda would be a quick fix for what digestive ailment?

"heartburn" caused by excessive stomach acid

The appropriate signalling that involves cAMP for water absorption in the intestine is disrupted by what toxin?

cholera

After enzymes act on proteins in the intestinal lumen, list every product of that degradation that gets absorbed into the intestinal cell.

single amino acids, dipeptides, tripeptides

Conversion to what molecule explains why alcohol consumption can cause fat deposits in the liver?

acetic acid (acetyl coA)

"Gastrin stimulates parietal cells to secrete HCl." In parallel, it stimulates chief cells to secrete what?

pepsinogen

Why might the nigrostriatal dopamine tract have to do with hunger/satiety?

contributes to motivation and affect

What indication of body energy stores would cause leptin to increase?

increased fat in adipose tissue

"Agouti-related protein (AgRP) is orexigenic." Translate.

this protein, oddly related to coat color, increases desire to eat

"The product of the parietal cells activates the product of the chief cells." Elabortate.

parietal cell puts out acid which converts chief cell's pepsinogen into pepsin

Why do some people occasionally drink a spoonful of baking soda mixed in water?

baking soda = "bicarbonate of soda" = sodium bicarbonate, neutralizes stomach acid, helps with "heart" burn

Away from emergency responders, what can you offer better than water to rehydrate a cholera victim?

an electrolyte-glucose coctail such as Gatorade is absorbed better

The microvilli on the surface of the intestinal cells are so famous that they have a name. What is that name?

Brush border

Why, in terms of chemistry or process involved, does hepatitis lead to jaundice?

inflammation has hepatocytes spill bilirubin (from hemoglobin recycling) into blood instead of feces

In terms of fat digestion, what is transported across the basolateral surface of the intestinal epithelium into the lacteal?

chylomicrons are triglycerides bound to proteins

You were shown that amino acids stimulated the G cell to release gastrin which caused the production of (what?) (also where?).

(via an intermediate ECL cell that releases histamine): acid in the stomach

"Agouti-related peptide (AgRP) is orexigenic." Explain to someone who is not as sophisticated as you (are supposed to be) either: The meaning of orexigenic. Or. How (in the heck) did we get on the topic of agouti?

opposite of anorexigenic, stimulating appetite. Although agouti has to do with coat color, this protein which is orexigenic is like agouti, hence that seemingly esoteric naming

For glucose absorption from the gut, what is the process on the basolateral surface that requires energy?

The sodium pump

Sometimes endopeptidases will cut off fragments that are two amino acids long. What becomes of these?

"In histology, you see zymogens located in acinar cells." What does that have to do with digestion?

These granules house the precursors of digestive enzymes of the pancreas

Relate the hepatic portal vessel with the "microsomal fraction" (smooth endoplasmic reticulum of the hepatocyte).

This gives the liver a chance to detoxify what is absorbed from the gut before it gets to the systemic circulation

"A lesion in the lateral hypothalamus (LH) gives you a thin rat, hence the LH is a hunger center." What have we learned since this conclusion was first reached that gives us a different view of the role of the LH?

The LH has the dopamine tract that is useful in motivation (affect) in general


this page was last revised 7/13/09

**The hormone lecture

Hormones

Fox Chapter 11, part of chapters 2, 9, 19, 20

Introduction

Metazoans (animals with more cells than protozoans) require systems of integration
INTEGRATION: Hormones, paracrine (local) & nervous system
"endocrine" - ductless, into blood stream
vs. exocrine (like digestive - saliva etc.)

Three steps:
cells with blood vessels for release
hormone transported in the circulation
target cell with receptor

Two mechanisms
(1) receptor molecule on membrane
(2) enter cell and bind receptor

Overview

TRANSPARENCY (From intro bio)

Fig. 11.1
I. Traditionally, this material starts with a picture of the major glands

II. Then it covers Pituitary three ways
(1) posterior pituitary
(2) anterior pituitary as "master gland" (and the other glands it controls)
(3) anterior pituitary (affects not mediated through other glands)

III. Then it covers other glands (not controlled by the pituitary)

IV. I will then give you a dose of "signal transduction" concentrating on steroids, thyroid and retinoic acid.

V. I will cover sex hormones in detail last (after glossing over them under II.(3) [above])

A later lecture outline, Reproduction, will take off beyond III. and V.

Posterior pituitary

Fig. 11.13
(related to kidney coverage)
neurosecretion from hypothalamus (peptides)
"suprachiasmatic" means over the optic chiasm
"paraventricular" means near the (third) ventricle
oxytocin (milk, delivery)
(synthetic to induce labor)
Covered in Excretion lecture: ADH action on kidney
vasopressin (ADH), H2O and blood pressure
alcohol, caffein inhibit anti [diuresis] hormone

Anterior pituitary

Fig. 11.15
Median eminence from hypothalamus to pituitary
Secretion of releasing (and inhibiting) hormones (peptides) at pituitary stalk
Portal system
Anterior pituitary and its hormones (peptides)

Fig. 11.14
(on right of figure) Master gland to show glands controlled by pituitary (thyroid, adrenals, ovary, testes) Trophic (tropins like "gonadotropins")
(on left of figure) not using other endocrine glands (Growth hormone and Prolactin)

Non-trophic hormones
(not where pituitary acts as master gland to control other glands)

GH - 200 a.a. -bone, muscle, not fat, -> liver to make somatomedins
GH - gigantism (bones grow long if too much GH when young), dwarfism (if too little GH when young), acromegaly (bones grow too thick if too much GH when already grown up, danger of GH abuse), abuse by body builders, dangers of extracts,, now available through recombinant DNA research

Prolactin - milk production, like GH (same ancestral gene)

Trophic hormones
(like gonadotropins) "Master Gland"
sex hormones from pituitary (more details later):
LH (female) = ICSH (male); (luteinizing) (interstitial cell)
FSH (follicle)
non-sex trophic hormones from pituitary:
TSH (thyroid)
ACTH (adrenal cortex)

TRANSPARENCY (From intro book)
Review - same material, intro course

Thyroid hormones

(recall that thyroid was used as hormone example in first lecture outline)
Influence on metabolism, but not as obviously as epinephrine, insulin, glucagon or even glucocorticoids.

Fig. 11.25
Negative feedback with pituitary
Hypothalamus -TRF-> + Ant. Pituit. -TSH->+ Thyroid -> thyroxine-
- neck thyroxin (T4), triiodothyroxine (T3) iodine, sea food (and iodized salt)

Fig. 11.3 (also shown in an earlier lecture)
T3 and T4

TRANSPARENCY (Figs 11.24, 11.26)
Goiter (thyroid overgrows if too little iodine in diet)
Cretinism if too little in infant, hypothyroid, hyperthyroid
Change in salmon during salt to fresh water change, metamorphosis in frog
Problem of radioactive iodine (like from reactor leaks) - helps to take large doses of non-radioactive iodine to compete

Adrenal gland

Fig. 11.20
Adrenal cortex - Glucocorticoids stimulate metabolism, inhibits inflamation.
JFKennedy had too little glucocorticoids (needed replacement therapy) which would create a situation of no feedback Addison's - too much ACTH (darkens skin like MSH).
pro-opiomelanocortin - big peptide cleaved to ACTH, MSH, endorphins, enkephalins
Emphasize regulation, negative feedback

Fig. 11.18
Zona glomerulosa - mineralocorticoids
Zona fasciculata and reticularis - glucocorticoids and androgens
Mineralocorticoids, the best known being Aldosterone helps kidney retain salt
Adrenalectomy causes salt loss and salt appetite.
Sweat glands are not as efficient at retaining salt as kidney.
That is why "Gatorade" (electrolyte) is used by athletes.
Salt is also lost in cystic fibrosis (mutation of CFTR (cystic fibrosis transmembrane conductance regulator)

Female reproductive cycle

good example of Regulation, Negative feedback
CHAULKBOARD DIAGRAM
Hypothalamus - RF's (peptides)
(chaulkboard diagram is also here, peptides in black, steroids in red)
Pituitary makes peptide hormones "gonado-trophic hormones" (gonadotropins, FSH and LH)
gonads (ovaries) make steroid hormones (estrogen and progesterone)
Feedback system plus effects on endometrium (lining of uterus)

FSH (follicle stimulating hormone) stimulates estrogen release from follicle
estrogen inhibits FSH
estrogen turns on LH (lutenizing hormone) release
estrogen begins buildup of endometrium
surge of LH causes ovulation
then follicle becomes corpus luteum that puts out progesterone
progesterone inhibits LH and FSH
progesterone also stimulates buildup of endometrium
to finish cycle, low FSH & LH which lets estrogen and progesterone go down
(corpus luteum starts to go away)
with low estrogen and progesterone, endometrium breaks down (menstruation)
with low estrogen and progesterone, pituitary is not inhibited so FSH starts
(if pregnant, HCG [human corionic gonadotropin] maintains corpus luteum
progesterone (from maintained corpus luteum) maintains endometrium
Here is a primary follicle, a growing follicle, the mature follicle, and the corpus luteum from our histology course.

Human corionic gonadotropin
Menstruation in primates
Estrus cycle - dogs heat 2x/yr, cats 3x/yr
Rabbits reflex ovulators
Pill Progesterone and Estrogen inhibit ovulation
28 day pill 7 duds: 1st 4 days, last 3
"combination pill"
Weight gain, circulation problems
lower proportion of estrogen
Rhythm - sperm viable 48 hr, ovum 15 hr: 3-4 day abstinance

The male pattern
FSH for spermatogenesis
LH (ICSH) to stimulate interstitial cells to release testosterone

Glands not controlled by pituitary

Adrenal medulla

Fig. 9.8
while on the topic of the adrenal gland,
Adrenal medulla (vs cortex under pituitary control)- Epinephrine, (alias adrenalin) - activates body
Autonomic (vs voluntary) motor control: sympathetic (vs parasympathetic)
Sympathetic nervous system uses norepinephrine at postganglionic synapses.
Sympathetic - "fight or flight"
Helps in metabolism to release glucose to blood stream
Muscles activity up, peripheral circulation and digestion inhibited
Heart rate goes up

Glucose (insulin and Glucagon) and diabetes
was moved from here to earlier

Calcium homeostasis

TRANSPARENCY (From introductory book)
Thyroid 2 glands (pituit - thyroxine TSH) vs:
Thyroid - thyrocalcitonin - blood Ca2+ down
Parathyroid - parathormone - blood Ca2+ up (from bones)
near thyroid gland in neck
Vitamin D sunlight, rickets, fish oil, hormone, absorption from gut
Osteoporosis - bone deterioration with age especially in women
Ca2+ very important, muscle (later), nerve (later)

Fig. 11.28
review, parathyroid hormone

Fig. 19.18b
PTH increases blood Ca2+
Osteoclast uses enzymes and acid to dissolve bone CaPO4

When calcium is needed a lot, bone depleted.
Osteoporosis, more common in women because of Ca2+ use in lactation.

Fig. 19.22
PTH effect on bone shown again here plus:
In kidneys, Ca2+ reabsorption is increased
and
In kidneys, 1,25-Dihydroxyvitamin D3 is made
(and that, in turn, increases intestinal absorption)

Working the vitamin D topic backward:

Fig. 19.21
kidney enzyme (1-alpha-hydroxylase) acts on 25-hyrdoxyvitamin D (from liver)

and

Fig. 19.20
Vitamin D from sunlight in skin
(plus liver and kidney shown in this figure)

Fig. 19.23
Calcitonin from the thyroid does the opposite

Steroids, etc

Fig. 2.23
structures of steroids
Structures of cholesterol, cortisol, testosterone, estradiol

Fig. 11.2
reactions of steroids
shows structures and locations of secretion
Interestingly, Cholesterol -> -> Progersteone (corpus luteum) -> ->Testosterone (Leydig cells) -> estradiol (follicles).

Fig. 11.5
steroid hormone receptor is protein that dimerizes
each receptor binds an HRE (hormone response element) (DNA sequence)
mechanism of hormone action is to activate gene transcription (into mRNA)

Estrogen

Menopause (pause in the menes) ["change of life" at about 50] - lack of estrogen.
(Some hysterectomy or ovarian cancer surgeries might also deplete because of ovarectomy).
Many symptoms, hot flashes most obvious short term effect.
Osteoporosis most obvious long term effect.
For me, this site worked with explorer, not netscape - estrogen (hormone) replacement therapy
Hotly contested (a lot of negative press lately), partly because estrogen increases chances of breast cancer.
There is a drug, Tamoxifen that blocks estrogen's effects, differently in different tissues.

Recent literature

J.L.Turgeon, D.P.McDonnell, K.A.Martin & P.M.Wise, Hormone therapy: Physiological complexity belies theraputic strategy, Science 304, 1269-1273, 2004
Estrogen and progesterone receptors in cardiovascular, neural, immune, gastrointestinal and musculoskeletal systems.
Menopause (average age 51) vasomotor flashes, vaginal dryness, urinary symptoms, osteoporosis, CHD (coronary heart disease.
Hence chronic estrogen therapy (ET) for CHD and osteoporosis.
A well intentioned study, WHI (women's health initiative) tested placebo, estrogen & estrogen-progestin.
Discontinued because of increase in breasst cancer, CHD, stroke and venous thromboembolism (but they did decrease fractures and colon cancer)
Human ovary: 17beta-estradiol.(E2) AND estrone (E1)
Study used conjugated equine estrogen (CEE) extracted from pregnant horse urine, many estrogens including sulfated estrogens.
Why this matters is that there are several types of estrogen receptors differentially activated by different estrogens.
Study used continuous oral administration, and hormone through hepatic portal system highly activates estrogen receptors in the liver, changing important proteins like angiotensin precursor.
Transdermal patch would be very different.
Women is study were fatter than usual.
Human progesterone vs study's medoxyprogersteone acetate (MPA), again affecting different receptors differently, also MPA activates glucocorticoid receptor.
There are several estrogen receptors, alpha and beta. and many ways they influence transcription.
"Antiestrogen" tamoxifen is antagonist in breast but agonist in bone and uterus, so now called SERM (selective estrogen receptor modulator).
Better SERMs are being found.

Androgens

Anabolic steroids - muscle growth, bone growth, increased hemoglobin
There is an androgen from the adrenal - DHEA dehydroepiandrosterone
Increased secretion of testosterone at puberty has many obvious effects including on larynx
Absence of androgens by castration decreases seminal vesicle and prostate
The whitish structure in this figure is the seminal vesicle
In this figure, the seminal vesicle of castrated and normal mice are compared

Fig. 20.14
Interestingly, many of testosterone's effects are mediated by estradiol-17beta, made by aromatase (in a process called "aromatization," note aromatic [in the organic chemistry sense] ring).
DHT (and several subsequent metabolites) made by 5alpha-reductase

Fig. 20.7
This step takes place in cells

When I typed "five alpha reductase" or the like into my search engine, I got hits on hair loss, concerning male pattern hair loss (androgenetic alopecia) accelerated by DHT and alleviated by a drug, Propecia

Some wierd disorders

5alpha-reductase deficiency -> "testes-at-twelve" (at puberty, testes descend, clitoris becomes penis etc when there is enough testosterone to overcome deficit) There is a pedigree in the
Dominican republic

androgen receptor mutation (androgen insensitivity syndrome [AIS]) -> testicular feminization, children think they are females until there is no menstruation

There are androgens from adrenal, so with Congenital adrenal hyperplasia, CAH, clitoris is large and behavior is "tomboy"

Signal transduction

TRANSPARENCY (From introductory book)
"gene"
sequence coding for protein (mRNA) is copied from exons with introns spliced out
"upstream" of gene, proteins binding promoter and enhancer regulate transcription

Fig. 11.4
steroid hormone
Carrier protein, receptor, DNA

Fig. 11.6
thyroid hormone
Carrier protein-T4, receptor-T3, DNA

Fig. 11.7
thyroid hormone
involves retinoic acid

Fig. 11.8
Remember signal transduction for G protein coupled receptor

TRANSPARENCY (From introductory book)
integrates the above point with epinephrine evolution of glucose

Prostaglandins, etc

Fig. 11.33
prostaglandins (mediators of inflammation) are derived from fatty acid (arachidonic acid, 20:4) using cyclooxygenase (COX)
Prostaglandins have different actions in different places; take platelet aggregation -- TXA2 stimulates clumping, PGI2 prevents them from sticking to walls of vessels; it is the TXA2 aspect that is why you take aspirin to prevent heart attack and should not take aspirin before surgery (etc.).
leukotrienes (mediators of inflammation) ... use lipoxygenase
NSAIDS (non-steroidal anti-inflammtory drugs) aspirin, ibuprofen, inhibit prostaglandin synthesis by inhibiting cyclooxygenase (COX-1 & 2) nonspecifically, problems in stomach
Celebrex, Vioxx, Bextra inhibit prostaglandin synthesis by inhibiting cyclooxygenase (COX-2); popular for arthritus, but Merck pulled Vioxx 10/04 for increasing cardiovascular problems, and later Bextra was pulled.
Aspirin is anti-inflammatory, anallgesic, antipyretic, anticoagulant, implicated in Reye's syndrome.

The Biology department's primary expert on endocrinology is Dr. Asa who is director of research at the St. Louis Zoo. As an adjunct Professor in SLU's Biology department, she teaches the popular course, "Introductory Endocrinology" BL A450-01

Exam questions from 2004 - 2008 relevant to this outline

Loss of what hormone would cause an adrenalectomized animal to crave salt?

aldosterone

What is the name of the disorder of too much growth hormone as an adult?

acromegaly

Vitamin D helps to keep the blood levels of what substance correct?

Ca2+

On what kind of molecule would you find a sequence known as a "hormone response element (HRE)?"

DNA

Historically, shortage of what mineral caused some inland people to develop goiter?

iodine

Why are alcoholic beverages contraindicated to stay hydrated in times of heat stress? (Make sure your answer says what happens to the relevant hormone level.)

alcohol inhibits ADH, more water is lost through kidney

Non-steroidal antiinflammatory drugs (NSAIDs) block converrsion of what fatty acid to prostaglandins?

arachidonic

After ovulation, the estrogen secreting follicle turns into a tissue that secretes what hormone?

progesterone

In the process where epinephrine causes glucose release from liver, what enzyme does cAMP activate?

protein kinase A

What kind of chemical is a gonadotropin?

peptide

The birth control pill feeds back to inhibit what pituitary peptide (to prevent maturation of the follicle)?

FSH

What does the osteoclast do to assist in Ca2+ homeostasis?

cause bone to release Ca2+

A receptor (protein) for T3 makes a heterodimer with a receptor for what substance?

retinoic acid

Hyperplasia of what gland would androgenize a female?

adrenal

What pituitary hormone maintains the cells that secrete testosterone?

LH

What syndrome results from 5a-reductase deficiency?

testes at twelve

What treatment has been standard for relief of hot flashes?

estrogen replacement therapy

Name one molecule in the biosynthetic pathway between cholesterol and testosterone.

progesterone

Within the ovary, what tissue produces estrogen?

follicle

Why is the term "anabolic" applied to some hormones?

growth (muscles, bone, hemoglobin)

Where are the cell bodies of the cells whose axon terminals release ADH and oxytocin?

hypothalamus

To mediate many of the effects of testosterone, aromatase converts it to what?

estradiol

After the alpha subunit of the heterotrimeric G protein binds GTP, what does it do to GTP?

breaks it to GDP (and P)

What close relative of retinal (retinene, the part of rhodopsin that absorbs light) is important in the activation of the hormone response element by triiodothyroxine?

retinoic acid

ACTH triggers the release of what hormone from its target gland?

cortisol

What is the tissue responsible for producing the gonadotropin that supports the corpus luteum early in pregnancy?

chorion

Why is such a small amount of thyrotropin-releasing hormone TRH needed?

because portal system delivers straight to anterior pituitary

Although dopamine is a transmitter itself, it can be converted into what other neurotransmitter by the enzyme dopamine beta-hydroxylase?

norepinephrine

What hormone would put calcium back into bones?

calcitonin

A surge of what peptide leads to ovulation?

LH

What second messenger activates protein kinase when the beta-adrenergic receptor of a liver cell binds epinephrine?

cAMP

Increased testosterone at puberty affect what organ to turn sopranos into altos?

larynx

What would happen to the TSH level if dietary iodine were deficient?

go up since negative feedback from thyroxine is decreased

What cleavage product of pro-opiomelanocortin would be high in Addison's disease?

ACTH

How would calcitonin regulate Ca2+ at the level of the kidney?

decrease resorption

In the term "gonadotropin," what does the suffix "tropin" refer to?

has trophic effect

What would happen instead of increase in bone length if growth hormone were too high in the adult?

bones would get thicker

In the old days, what would cod liver oil be used for?

vitamin D (and A) replacement

In the pathway 7-dehydrocholesterol -> vitamin D3 -> 25-hydroxyvitamin D3 ->1,25-dihydroxyvitamin D3, where does the first conversion take place?

in the skin

Osteoclasts contribute to the breakdown of CaPO4 plus what additional component, a protein, in bone?

collagen

A surge of LH mediates ovulation plus the conversion of the follicle into what tissue?

corpus luteum

What is it called when, because of low progesterone, the endometrium is no longer supported?

menstruation

What hormone supports the endometrium during pregnancy?

progesterone

What effect does calcitonin have on the kidney?

Allows for CaPO4 loss in urine

Testosterone is converted to dihydrotestosterone (DHT) by what enzyme?

5-alpha-reductase

Tamoxifen used to be called an antiestrogen but might now be better referred to as a SERM (selective estrogen receptor modulator). Why?

antagonist in some tissues but agonist in others

A heterodimer of receptors for thyroid hormone and retinoic acid (together with their respective ligands, thyroid hormone and retinoic acid) binds to what specific location on what molecule?

response element on DNA

Estradiol-17b is made by aromatase from what steroid (the immediate precursor)?

testosterone

Give a reason why the exact same mixture of hormones might have different effects in a woman if given orally vs via a transdermal patch.

would go to liver by hepatic portal vessel if taken by mouth

A steroid hormone receptor is famous for binding the hormone as well as what major macromolecule?

DNA

Give the name of a class of molecules produced by enzymes acting on arachidonic acid (20:4).

prostaglandins (leukotrienes)


What type of chemical is the product of the Leydig (interstitial) cells?

steroid

In terms of how they inhibit prostaglandin synthesis, how would a COX2 inhibitor differ from traditional NSAIDS like aspirin?

aspirin was non-specific (COX1 & 2)

Chemically, what type of molecule is a gonadotropin?

peptide

Where is the receptor for steroid hormones?

inside the cell

What would be the most common reason to administer oxytocin (or a synthetic version of this hormone)?

induce labor

Why would very small amounts of TRH be needed for adequate homeostatic control?

portal vessel from hypothalamus to pituitary means that it is not diluted by the systemic circulation

Although steroids in the birth control pill would have a trophic effect, building up the endometrium, they block pregnancy. By what mechanism?

by inhibiting FSH and LH, they prevent ovulation

What is the effect of the hormone of the adrenal medulla on heart rate?

adrenalin increases heart rate, of course

A lot of hormone from the parathyroid gland would decrease calcium in what notable reservoir in the body?

bone

Ovulation, as well as the conversion of the follicle to the corpus luteum, is induced by a surge in what pituitary peptide?

LH

PTH, the hormone of the parathyroid, acts on the kidney to stimulate Ca2+ reabsorption and inhibit PO4- reabsorption. What other effect does PTH have on kidney to help to increase plasma Ca2+?

formation of 1,25-dihydroxyvitamin D3 (increase 1alpha-hydroxylase activity

What famous steroid hormone is an intermediate in the conversion of progesterone to estradiol-17beta?

testosterone (also androstenedione)

A DNA-binding domain is a hallmark of what kind of molecule that binds to a hormone response element?

steroid hormone receptor protein

Testosterone is converted by 5alpha-reductase or by aromatase into (name one of these steroids)?

dihydrotestosterone, estradiol-17beta

How does cAMP activate the kinase?

binds to and removes inhibitory subunit from catalytic subunit

Answer one of the following for the precursor that cyclooxygenase turns to prostaglandins and lipoxygenase turns into leukotrienes - (1) name it, or (2) say what kind of molecule it is, or (3) where does it come from?

arachidonic acid ((20:4), fatty acid, from membrane phospholipid

Who would suffer from acromegaly?

adults with too much growth hormone

Why would your skin be dark if you had Addison's disease (inadequate cortisol, no feedback, too much ACTH)?

ACTH mimics melanocyte stimulating hormone

Chemically, what type of hormones are the hormones of the adrenal cortex?

steroids

If estrogen and progesterone maintain the endometrium, how come women taking the birth control pill still have menstruation?

estrogen and progesterone are not given for a few days

Why would hyperplasia of the adrenal masculinize a female?

adrenal cortex makes anabolic steroids like testosterone, too much if there is hyperplasia

Why is the area upstream of a gene's coding sequence relevant to the actions of retinoic acid, thyroxine and steroid hormones?

this area is the promoter where steroid hormone receptors , retinoic acid receptors, etc bind

The G protein coupled receptor signals to the next molecule in the cascade, namely the G protein. Why is it called a G protein?

binds GTP

Why is the term "neurosecretion" used for some hormones and give one example.

neurons with axons release chemicals from their terminals near blood vessels, ADH, oxytocin, releasing hormones

What happens if there is too much growth hormone in the fully-grown adult?

bones grow in thickness, not length, acromegaly

What leads to hypertrophy of the thyroid gland (goiter)?

deficiency of iodine

Why do they need to build fish ladders beside tall dams?

salmon go up their native stream to spawn

What type of chemical is the hormone secreted by the follicle?

steroid

After implantation, what peptide stimulates the corpus luteum to continue progesterone secretion?

human chorionic gonadotropin

What important cell, other than the hormone-secreting cells, is present in the follicle?

the egg

What type of chemical is the hormone that has a trophic effect, causing the Leydig cells (interstitial cells) to release their hormone?

peptide

H2CO3 is split in osteoclasts. Where do the two portions go and why?

H+ for acidity into bone on one side of the osteoclast, HCO3- exchange with Cl- on the other side to start Cl- toward the bone to make HCl

Which hormone from a gland inside the neck has the same effect on plasma calcium ion concentration as 1,25-dihydroxyvitaminD3?

PTH

Describe why the system of the hepatic portal vessel might be relevant in estrogen replacement therapy.

Any chemicals, if taken orally, might be converted to other things by the liver

Testosterone gets converted to other steroids for its activity. Tell me one of the enzymes that effects these conversions.

5-alpha reductase (to 5 alpha DHT) or aromatase (to estradiol-17beta

One part of the retinoid X receptor (RXR) binds 9-cis retinoic acid. What does the other part of this molecule bind?

DNA (the RARE)

Why doesn't the alpha subunit of the heterotrimeric G protein activate the adenylate cyclase indefinitely?

it has GTPase activity (etc.)

Why would a selective estrogen receptor modulator (SERM) be so potentially useful for bone health?

have the beneficial effect on osteoblasts but not promote breast cancer or cardiovascular problems

Why might you want to inhibit the normal function of osteoclasts?

to stave off osteoporosis

Many hormone receptors are on the cell membrane. How can steroid hormone receptors work when they are inside the cell?

by binding steroid hormones and also binding DNA at hormone response element

ACTH is cleaved from what peptide precursor?

proopiomelanocortin

What organ are the steroid-secreting zona fasciculate and zona reticularis part of?

adrenal cortex

Out of a long laundry list, tell me one precursor of the hormone from the adrenal medulla.

tyrosine, l-DOPA, dopamine, norepnephrine

Tell me one of several molecules that are precursors for all of these: hydrocortisone, testosterone, and estradiol-17beta.

cholesterol, pregnenolone, progesterone

"A gene is the coding sequence for a protein." The truth but not the whole truth. Relative to this, where is the hormone response element?

upstream of the coding sequence

What is the precursor of leukotrienes, and where (in the cell's anatomy) does it come from?

arachidonic acid, in membrane lipid

Why did COX-2 inhibitors show so much promise, and why were some pulled from the market?

reliece arthritic inflammation without interfering with gastric mucosa, increased chance of heart attack

By what mechanism is estrogen good for bones?

it promotes osteoblasts

What is it called when a hypothyroid condition as an infant leads to deficient neural development?

cretinism

What is the condition where there is too much ACTH? - Answer one: (1) name of condition (2) What is there too little of? Or (3) Why does the skin get dark?

Addison's disease, too little cortisol, ACTH is like MSH (melanocyte stimulating hormone)

The adrenal cortex is famous for producing androgens, glucocorticoids and (what else?).

mineralocorticoids (aldosterone)

Norepinephrine is converted to epinephrine to be the major hormone of what (specific) gland.

Adrenal medulla

Why would cod liver oil be a useful dietary supplement for some people?

Vitamin D

Why was there the conventional wisdom that estrogen by patch was safer than oral administration?

Swallowed, the liver could make many other products

Why was the women's health initiative study discontinued?

Increase in breast cancer, coronary heart disease

For "androgenic alopecia" tell me either (1) what these words mean, or (2) what an enzyme or the hormonal product it catalyses has to do with that.

Male pattern baldness, 5 alpha reductase makes DHT

Address the terms "paraventricular" and "supraoptic" in ONE of the following ways: (1) What part of the brain are they in? (2) How did those nuclei get those names? (3) What structure is the output of this neurosecretion? Or (4) What are the hormones?

hypothalamus, around the (third) ventricle and above the optic chiasm, posterior pituitary, ADH or oxytocin

For one portal system, the first capillary bed is in the pituitary stalk. Answer ONE of these (1) Where are the cell bodies responsible for secretion into this vascular bed? Or (2) Where (specifically) is the second capillary bed?

hypothalamus, anterior pituitary

Distinguish between what happens with too much growth hormone as a child vs as an adult.

become a giant, acromegaly

How come women who took the birth control pill still menstruated?

out of the 28 days, the steroids are not in the last 5 days so the endometrium is not supported

What are the two different functions of the pituitary gonadotropins in the male?

FSH spermatogenesis, LH getting the interstitial cells of Leydig to secrete testosterone

A surge in LH converts the follicle to the corpus luteum and (what else does it achieve?).

causes ovulation

Why doesn't the endometrium break down once FSH and LH stop maintaining the corpus luteum when implantation has occurred?

HCG supports the corpus luteum, so there is still progesterone

Starting with 7-Dehydrocholesterol, what is the order of action of the 3 separate ORGANS in the production of the active form of vitamin D?

skin, liver, kidney

A hormone from the thyroid has (what effect on the kidney?) for calcium homeostasis.

calcitonin stimulates excretion of Ca2+

Progesterone is the precursor of what two sex steroids?

testosterone and estradiol

Where, specifically, is the hormone response element?

on the DNA upstream of the coding sequence for the protein

Why would a mutation in the receptor that caused insensitivity to androgens have the effect it has in androgen insensitivity syndrome?

testicular feminization b/c there is no response to hormones like testosterone

Why at the time, was the availability of new COX-2 inhibitors heralded as such an important development?

arthritis symptoms taken care of without the COX-1 interference with the gastric mucosa

The thyroid receptor makes a heterodimer with a receptor for what signaling molecule?

retinoic acid


this page was last revised 7/21/09

** The reproduction lecture

Animal Reproduction and development

From speech of Aristophanes:
...The sexes were not as they are now...the primeval man...had four hands and four feet, one head with two faces...Terrible was their might and strength...and they made an attack upon the gods...Zeus...said: "Methinks I have a plan which will humble their pride and improve their manners; men will continue to exist, but I will cut them in two...After the division of the two parts of man, each desiring his other half, came together, and throwing their arms about one another, entwined in mutual embraces, longing to grow into one...
-Plato Symposium

Love (sweet Chloe) is a god, a young Youth, and very fair, and wing'd to flye... His power's so vaste, that that of Jove is not so great... For there is no med'cine for Love, neither meat, nor drink, nor any Charm, but only Kissing, and Embracing, and lying naked together.
-Daphnis & Chloe By Longus Translated out of Greek by George Thornley Anno. 1657

Fox Chapter 20

MALE

Meiosis and sperm

Fig. 20.16
Spermatogonia (mitosis and meiosis) - primary spermatocytes
- meiosis (both divisions) - spermatids (scrotum cooler)
Sperm (meioses throughout adult life) Seminiferous tubules
300 million/ ejaculation

Fig. 20.13
Testes - seminiferous tubules make sperm, stimulated by FSH, inhibin for feedback
Interstitial (Leydig) cells produce testosterone, stimulated by LH (ICSH), feedback

Fig. 20.12
Low mag section of testis, higher mag showing seminiferous tubule and interstitial cells
Testes in short day hamsters are smaller than in long day hamsters

Fig. 20.17
An even higher magnification showing Sertoli cell that supports spermiogenesis, has histology
(histology picture)

Semen

Fig. 20.20
male anatomy
Semen:
Bulbourethral (Cowper's) gland (early overflow from sexual excitement)
Seminal vesicle - fructose, amino acids, mucus, prostaglandins (uterine contractions)
Prostate - alkaline (infection, cancer most men > 50)
Capacitation of sperm
Epididymis
Vas deferens - peristalsis -(vasectomy 100% effective- permanent long term effects unknown)
Urethra (of course, it is output here for which condom is a form of contraception)

The prostate story.

Cancer in men >50, diagnosed by paplation
PSA=prostate specific antigen, 1 is low, 5 is high, but not specific to cancer, might be high after having sex
Several "remedies" including selenium
Surgery and radiation, etc.
Slowly developing cancer
Complications - incontinence (for #1, even #2), possibly impotence (ED)
For ED, Viagra, Levitra, Cialis

Fertilization

Many sperm attack one egg, only one fertilizes - fast (electrical) response prevents others

20.39
acrosome, nucleus, mitochondria (not go into egg), flagellum

Review:
Parasympathetic arterioles (unique, usu only symp.) - erection (sleep)
ACh - NO - smooth muscle dilate- viagra blocks breakdown enzyme
NO synthase in cavernous artery and corpus cavernosum
Robert F. Furchgott, Louis J. Ignarro, Ferid Murad Nobel 1998 "for their discoveries concerning nitric oxide as a signalling molecule in the cardiovascular system"
Sympathetic - ejaculation inhib erection

Fig. 20.21
Here is a picture from our histology course showing the spongy tissue of the corpus cavernosum which becomes engorged with blood to mediate erection.
rodents racoons walruses - bone
Sympathetic - ejaculation inhib erection

FEMALE

Review

Fig. 20.34
Here is the typical text book diagram depicting the menstrual (ovarian) cycle (covered earlier)

For convenience, I used the term "eggs" earlier, now I get more official

Meiosis, ovary, steroids

Fig. 20.32
I showed this to you before
primary oocyte in early follicle
secondary oocyte in mature follicle

Fig. 20.31
Here's how that relates to meiosis
Primary oocyte (2-4 million at birth, 1st meiotic prophase)
(400,000 at puberty, only 400 used)
(no oogonia after 3 mo)

Secondary oocyte + polar body
(Graffian follicle finish 1st meiosis) ovulation
if 2 ovulations - DZT - 2 amnions, 2 chorions
twins 1.2% of births, of these 70% "fraternal"
DZT run in family

Uterus, fertilization, and early development

Fig. 20.24
Review
I showed this to you before
anatomy of ovary, and relation of ovulation to fimbriae of uterine (Fallopian) tubule
Tubal ligation (laparoscopy) 100% effective. Reverse?
Cervix (diaphragm, cervical caps, foam, spermicidal jelly)

Fig. 20.42
Fallopian tube (fimbria capture ovulated egg - Sperm meets, 2nd meiosis makes ootid 3 polar bodies discarded nucleii
Division in Fallopian tubes
Blastocyst (trophoblast, blastocoel, inner cell mass)
(trophoblast - >chorion -> placenta)
(inner cell mass -> embryo -> fetus)
IUD prevent implantation, irritate, after previous child, not for everybody legal question
if inner cell mass divides, Monozygotic (identical) twins MZT (2 amnions, 1 chorion), 30% of twins

Fig. 20.44
Shows trophoblast, implantation and a little development

While I have this up, I will talk about "stem cell research"

This relates to cloning.

Cloning

(Not cloning as in cloning a gene, but cloning an organism)

1950's work on amphibians - Since all nuclei should have all the genes, any nucleus should work to make whole organism, taken out of, for instance, an intestine cell. But not all cells work, so put the nucleus into an egg where it is certain that the nucleus already there has been destroyed.

work to make sheep Dolly. Nuclear transfer by removal of egg nucleus followed by fusion with cell with diploid nucleus. Need to implant into a surogate mother.

Cloning has been extremely controversial, and human "reproductive cloning" is banned. Some scientists hoping to advance medical treatments would like to distinguish "theraputic cloning" from cloning to produce a person genetically identical with the donor. Some think the issue would be simplified by use of the term "nuclear transplantation."

Stem cell research

Because cells lose their pluripotency, researchers have focussed on their discovery that embryonic stem cells are better at differentiating into cells that can repair cell damaged areas such as in the case of spinal cord injury; the issue is very controversial because it may encourage practitioners to create and destroy human embryos for no other purpose than to harvest stem cells. Of note, there may be "left-overs" (it is hard to find a diplomatic euphemism) from in vitro fertilization after a couple has had all the children they want (that might go to "waste"). For this reason, for humans, only the use of some 60 cell lines that are already in culture was dictated in the US by President Bush.

Several colleagues and I are collaborating to cure blindness in a mouse mutant with cells that started as embryonic and were induced to become precursors of nerve cells; identified by green fluorescent protein, here is a cell that has been put into the retina and is beginning to show a neuron-like phenotype.

Cursory overview of development

Fig. 20.46
trophoblast implants becomes chorion -
Chorionic villus biopsy - early genetic testing
Amniocentesis-later genetic screening
placenta - exchange, diseases like rubella, alcohol, drugs

Fig. 20.45
make HCG 2 wks - 4 mo (pregnancy test)
to maintain corpus luteum

Fig. 20.5
(not graphic)
2 sexes from 1 primordium
H-Y antigen = testes differentiating factor
then testosterone alters development
MIF (Mullerian inhibiting factor) contributes to development of male "plumbing" female pattern is the default pathway, clitoris is equivalent of penis

Prof Aldridge teaches several courses and does research on reproduction. Prof Ogilvie teaches developmental biology. Prof. Schreiweis teaches embryology.

Exam questions from 2004 - 2008 relating to this outline

How many oogonia does a woman have at puberty?

none

A ball consisting of trophoblast plus what other clump of cells becomes implanted in the endometrium?

inner cell mass

When is meiosis completed in the "egg?"

when sperm meets egg

A low PSA reading is around 1 while a high PSA is 5. What does PSA stand for?

prostate specific antigen

Where is the acrosome?

tip of spermatozoan

Why might a physician want to test a sample of amnionic fluid?

to test prenatally for gene or chromosomal defects

Semen has components from seminiferous tubules, seminal vesicles, bulbourethral (Cowper's) gland, and what other gland?

prostate

The trophoblast becomes the chorion, and the chorion, in turn, becomes what?

placenta

What divides to make monozygotic (identical) twins?

inner cell mass

Where does fertilization take place?

way up in uterine (Fallopian) tube

What becomes of the mitochondria of the spermatozoan during fertilization?

they do not go into the egg

Incontinence is a common consequence of what surgery?

prostate

What is the result of ligating and snipping the vas deferens?

man is no longer fertile

Where is the "egg" when meiosis is complete?

when the sperm fuses

What divides to make identical twins?

inner cell mass

Genetically, how are fully differented adult cells different from pluripotent stem cells?

They both have the same genes, though only a limited subset are being expressed in the former

One diploid primary oocyte undergoes two meitic divisions. How many cells that can be fertilized result?

only one

What part of the blastocyst will eventually (much later) become the placenta?

trophoblast

How can a physician test for defects earlier than amniocentesis?

chorionic villus biopsy

What happens if neither MIF (Mullerian inhibition factor) nor testosterone are present?

primordia of sex structures adopt female development

The PSA (prostate specific antigen) test is used to diagnose a predisposition for what disorder?

prostate cancer

Why is development of uterus and clitoris considered the default pathway?

testes-determining factor (TDF), Mulleriasn-inhibiting factor and testosterone actively cause indifferent gonad primordia to select the male pattern

Spermatogonia undergo meiosis to make sperm. In what way is this process different for formation of oocytes in the adult human?

There come to be no oogonia in women, thus the entire meiosis does no occur throughout life, way fewer gametes are formed, 4 sperm vs 1 oocyte and polar bodies, sperm constant oocyte meiosis regulated when sperm meets egg

Name one of the glands that adds to sperm to make semen.

bulbourethral (Cowper's), seminal vesicle, prostate

Nitric oxide activates an enzyme that makes cGMP. (Maybe you did not know this.) Why might some people take a drug to inhibit the enzyme that breaks down cGMP?

for erectile dysfunction

Why is the IUD (intrauterine device) particularly controversial?

prevents implantation, not fertilization

Say where (or when) the second meiotic division occurs for the oocyte

uterine tubule, when sperm meets egg

What technique provides earlier information on genetic or chromosomal abnormalities than amniocentesis?

chorionic villus biopsy

What specific body of cells divides to make monozygotic (identical) twins (and also is a source of embryonic stem cells)?

inner cell mass

What is the "egg" called officially at the time of ovulation, and what stage of meiosis or mitosis is it at at that time?

secondary oocyte, before meiosis II is complete

Tell me about oogonia in the human female between the first menstrual period and menopause.

there are none

Why do proponents think that embryonic stem cells might be useful to treat Parkinson's disease.

such cells are pleuripotent

An embryonic structure becomes the penis if testosterone is present. What does it become without testosterone?

clitoris

Tell me about spermatogonia in the adult male.

diploid, replace themselves by mitoses, give rise to diploid primary spermatocytes

Ligation and cutting of what tube is a common elective surgery for men to achieve sterility?

vas deferens

Why might an elderly man decide not to have surgery after first being diagnosed with prostate cancer?

it progresses slowly, surgery has side effects

Ovulation comes after a striking surge in what gonadotropin from where?

LH from anterior pituitary

Where (anatomically) does fertilization take place in the human.

in the uterine (fallopian) tube

How do dizygotic (fraternal) twins come about?

2 ovulations

Birth control prevents fertilization. Why is the intrauterine device qualitatively different?

prevents implantation meaning that fertilization (and many cell divisions) have already taken place

In cloning (Dolly, for example) what do you put into the surrogate mother and where?

blastocyst to uterus

"Spermatogenesis: the formation of spermatozoa, including meiosis" (from the glossary in your book). How is spermiogenesis distinguished from spermatogenesis?

spermiogenesis is just the stripping of the cytoplasm of spermatids and the streamlining of spermatozoa

For purposes of family planning, some men elect to have a straightforward surgery that results in sterilization. What is done?

vasectomy = ligate and sever the vas deferens

Why might an elderly man decide not to have surgery for prostate cancer?

it is a slowly developing cancer, and possible side effects of impotence and incontinence detract from the quality of life

As the sperm cell is about to fertilize the "egg," how far along in its meiotic divisions is the egg?

arrested at metaphase II (i.e. meiosis I is complete, but not II)

When are primary oocytes formed from oogonia in the human female?

before birth

With the intrauterine device, which irritates the uterus, the likelihood of an ectopic pregnancy is increased. How does ectopic differ from normal?

way up in uterine (fallopian) tube (instead of uterus)

What is the specific source of embryonic stem cells?

inner cell mass

What is the difference between identical vs fraternal twins in how they are formed?

two ovulations both fertilized fraternal, inner cell mass divides identical

Why do researchers have high hopes for the use of embryonic stem cells for eventual therapies for disorders like retinal degeneration and Parkinson's disease?

they are pluriotent, amazingly form into needed cells if placed where they are needed

Why should cells in the amniotic fluid give us information about genetic (and chromosomal) abnormalities of the fetus (and not the mother)?

the amnion (and of course the fetus) are of zygotic (as opposed to maternal) origin, so the fluid is surrounded only by cells from the fertilized egg

Under the influence of Mullerian inhibition factor (MIF) and (what else?) male development is initiated instead of the female default pathway.

testosterone

How do the mitochondria in the sperm cell contribute to the DNA in the zygote?

They do not

Two meiotic divisions in the female result in only one "egg." What did the other nuclei produced by meiosis become?

Polar bodies

In cloning Dolly, an egg was obtained, its nucleus was removed, a somatic cell nucleus was put in, and cell divisions create an embryo (a hollow ball of cells) in vitro. What did they have to do after that so that a sheep was born?

Implant into a surrogate mother

Why would the intrauterine device (IUD) be considered to be particularly controversial?

Well, even blocking fertilization might be controversial, but blocking implantation is a really early abortion

Why does in vitro fertilization come up in discussions of the benefits and controversities of stem cell research?

One possible source of embryonic stem cells would be "left overs" once a couple has decided they have had enough children



this page was last revised 7/28/09

** Blood and the immune system outline

Blood and antibodies

Fox Chapter 15 (immune system)
also part of Chap 13 (for blood)
A figure from Chapter 20

Fig. 13.1

Overview of blood cell types

plasma and hematocrit (formed elements), Buffy coat between

I. Plasma - (serum lacks fibrinogen) fluids, nutrients, O2, CO2, ions
proteins (synthesized in liver except gamma globulins)(clotting)
Albumins
Globulins
Fibrinogen

II. Hematocrit
Erythrocytes 5-6 million/ml
Leucocytes 5-10 thousand/ml
Platelets 250,000-400,000/ml formed from megacaryocytes
(antibodies) ions, wastes, hormones

Blood clotting

Fig. 13.9
Platelets 250,000/ml from megacaryocytes
Clotting Platelet adhesion then fibrin (from fibrinogen)
Cascades
activated Hageman factor
prothrombin -> thrombin
fibrinogen ->fibrin
Hemophelia is famous disorder

Hemophelia (4 SLIDES)
pedigree
Victoria, Nicholas II & Alexandra - Alexis, Rasputin
on X
problem with AIDS for clotting factor

Erythrocytes

Fig. 13.3
Red blood cells (corpuscles) (erythrocytes)
no nuclei
O2 transport, hemoglobin, anemia
last 120 days, made in marrow, recycled
iron recycling in liver is what makes feces dark (and skin yellow in jaundice [hepatitis]) - bile pigments

Polymorphonuclear granulocytes

There are non-specific responses to injury

White blood cells (leucocytes as in leukemia)
Polymorphonuclear granulocytes (phagocytosis, etc)
neutrophil (60-70%) phagocytosis
here is a picture from our histology course of a neurtophil showing the complex nucleus

Fig. 15.2
chemotaxis after 30-60 min
more synthesized especially in bacterial infection
reset thermostat (pyrogens)
eosinophil (1.5%) phagocytosis
allergic and parasitic inflamation
basophil (0.1%) histamine containing
like mast cells

Phagocytosis and review slides

Fig. 15.1
Phagocytosis (cell eating), fusion of primary lysosome, formation of secondary lysosome

SLIDES: blood cells (SEM= scanning electron micrograph))
white blood cell engulfing bacterium (Light Micrograph)
same (SEM)
SLIDES macrophage eating E. coli
macrophage - asbestos
fibrin (2 slides)

Monocytes

Fig. 15.6
Mononuclear cells
monocytes (5%) (as in mononucleosis) (phagocytosis)
late chemotaxis become macrophages
alveolar macrophages in lungs
Kupffer's cells in liver

Inflammation

Fig. 15.5
Inflammation and phagocytosis
Triad redness, warmth, swelling
Histamine (from mast cells, platelets)

lymphocytes:

There are specific responses involving antibodies and other mechanisms

T-cells (80%) (thymus - near heart) cell
(transplant) cytotoxic, suppressor, helper (AIDS)
B-cells (20%) (bone marrow, actually bursa of Fabricius) (become plasma cells)
antibodies

Blood groups

Fig. 13.5
Blood groups
This topic is fundamental and a bit confusing.
genotypes IA IA or IA i have phenotype A, A antigens, anti-B antibodies
genotypes IB IB or IB i have phenotype B, B antigens, anti-A antibodies
genotype IA IB has phenotype AB, A and B antigens, no antibodies
genotype ii has phenotype O, no antigens, antibodies to both A and B
O universal donor, AB universal recipient
There are already antibodies since blood group polysaccharides are like those of bacteria even though there was no previous exposure to antigens. IgM not cross placenta

Rh factor

- mother and + fetus problem if blood crosses over (during delivery)
problem is next time since IgG crosses placenta
treat mother with antibodies (passive immunity) then she will not mount active immunity

Active and passive immunity

When I was a kid, nearly everrybody got measles, mumps, and chicken pox. We were presumably immune for life (active immunity). When we had the disease was part of out health record.

Vaccines - active immunity (like disease)
memory cells of immune system
Edward Jenner 1796 "encowment"
Farmers were less likely to get smallpox because they got a related disease, cowpox
When I was a kid, you could not enroll in school without the scar
Smallpox is so completely eliminated that one issue is whether to get rid of lab virus.

When I was a kid, there was (still) a polio epidemic.
A kid at a birthday party I went to got polio, so I went to the family doctor for gamma globulin, passive immunity
(1954 Salk vaccine injected, soon Sabin vaccine in sugar cube)

Fig. 15.15
lymph system and nodes

Antibodies

Humoral immunity - B cells

Fig. 15.23
clones of plasma cells and memory cells derived from B cells for specific antigens

Fig. 15.7
Another version of this figure

Fig. 13.4
(showing only erythrocytes)
Interesting continued development through life of monocytes, granulocytes and lymphocytes from stem cells
note, the bone marrow which makes blood cells is mostly in the head and ribs, the two most likely locations for X-rays which are dangerous

Fig. 15.8
Antigen (virus or bacterial coat, usually not self)
Antigenic determinant (epitope 5-15 anino acids)
IgD on B cells, antigen receptors

Fig. 15.10
Antibody
2 long chains and 2 short chains, variable region at the end of all 4 makes it specific for antigen
An amazing mechanism where the gene is rearranged accounts for diversity.
IgG most abundant, monomer, cross placenta

Fig. 20.55
Antibodies cross placenta, also in mother's milk, and late weaning covers until child's own antibodies are formed.

Fig. 15.26
IgE allergy, bind to mast cells (histamine)

T-cells

Fig. 15.17
helper T cells express CD4
antigen presenting macrophage
MHC major histocompatability complex 20 genes 50 alleles each
Class II MHC only on macrophages (and B lymphocytes)
antigen presented by to B cell

Fig. 15.18
cytotoxic (killer) T cells express CD8
Class I MHC - actually on lots of cells (including the infected cellsshown here)
[try to match MHC (tissue typing) for transplantation]

Fig. 15.19
Interleukin-2 is released by helper T cells to cause killer and helper cells to proliferate

Exam questions from 2004 - 2008 related to this lecture

What kind of cell becomes a macrophage?

monocyte

Presence of what in type O people would lead to agglutination if there were a transfusion with any other type of blood?

anit-A and anti-B antibodies

Presence of what in type O people would lead to agglutination if there were a transfusion with any other type of blood?

anit-A and anti-B antibodies

Eosinophils are a type of polymorphonuclear granulocyte. What is eosin?

a histological stain

What kind of molecule is IgG? (Be more specific than "protein.")

antibody

In a neutrophil or macrophage, after phagocytosis of a bacterium, what cellular organelle full of enzymes fuses with the phagosome to destroy the bacterium?

lysosome

A B lymphocyte develops into what protein-producing cell?

plasma

When it is needed, what important protein does a plasma cell export?

antibody

What cell is specifically depleted in AIDS?

Helper T

The first vaccination was for what disease?

small pox

What are the two types of lymphocytes?

B&T

For Rh, a second exposure is very serious. Why is a first exposure, like a transfusion of the wrong blood group, bad in ABO blood groups?

there are already antibodies

A bacterium is engulfed into a vacuole in a phagocytic white blood cell. What cellular organelle, a bag of acid hydrolases, fuses with this endosome to destroy the bacterium.

lysosome

Like neutrophils, monocytes infiltrate the injury site, attracted by chemotaxis. What is the difference in timing?

monocytes are later

Considering how much fibrin is around when clotting is needed, how come fibrin does not make blood clot all the time?

unless cleaved by clotting cascade, fibrinogen is inactive

Macrophages are derived from what type of white blood cell?

monocytes

Why are the prospects for worldwide elimination of flu by immunization more elusive than for smallpox or polio?

evolution of virus in alternative hosts like birds and pigs

Antibodies produced by plasma cells are ineffective against infected cells. What specific type of lymphocyte destroys such cells loaded with foreign bacteria or viruses?

killer (cytotoxic) T lymphocytes

Class 1 & 2 MHC (major histocompatibility complex) molecules are expressed on the surfaces of various cells. Why is it almost guaranteed that yours are different from mine?

many genes, many alleles of each

If type A red blood cells are transfused into a type B person, antibodies in the type B blood will cause the red blood cells to clump. What is this clumping called?

agglutination

What is the chemical signal that the helper T cell uses to cause the appropriate type of killer T cells to proliferate?

interleukin 2

Which specific antibody crosses the placenta to give the baby the mother's immunities early in life?

IgG

In what way is IgG different from IgM with regard to the placenta and blood groups?

IgG for Rh cross, IgM for ABO not cross

"Monocytes have a late chemotaxis and form macrophages." Translate.

these white blood cells are attracted to the site of injury after polymorphonuclear granulocytes and further develop into big phagocytic cells

Which specific type of white blood cell is depleted in AIDS (acquired immunodeficiency syndrome)?

CD4-expressing (helper)

Why are lysosomes an important part of phagocytic leukocytes?

they merge with endosomes to digest them

What kind of immunity does RhoGAM confer in the treatment for Rh- mothers?

passive

Why is there a major difference between small pox and flu (influenza) with respect to the prospects for total elimination of the disease from the worldwide human population?

flu evolves and has alternative animal hosts

What purpose does IgD on the surface of B cells serve?

it is the antigen receptor

An allergen binding to IgE on the surface of mast cells causes the release of what substance from its granules?

histamine

Class II MHC (major histocompatability complex) is expressed only on macrophages and B lymphocytes. What about class I?

all cells, involved in attack on infected cells

Why is AB the universal recipient?

no A or B antibodies

Neutrophils, eosinophils and basophils are all white blood cells. Name a different type of white blood cell.

monocytes, lymphocytes (B and T)

Why is there so much variability in the MHC (major histocompatability complex)?

20 genes, 50 alleles each

Why is it beneficial for the infant that IgG crosses the placenta and that IgA is in mother's milk?

passive immunity from mother

CD8 vs. CD4 coreceptors distinguish what types of cell?

Killer vs helper T cells

What is agglutination as it applies to antibodies and the blood groups?

antibody causes cells to clump

We don't worry so much about blood type (ABO) of the fetus vs the mother, but we do worry about Rh factor. Why the difference?

IgM does not cross placenta, IgG does

For what is IgE most relevant?

allergy

How can MHC be so variable?

20 genes 50 alleles each

If all goes as "intended," what happens to a bacteria-containing endosome in a white blood cell?

becomes secondary lysosome after merging with primary lysosome (etc.)

Which blood cells are the precursors of macrophages?

monocytes

Some bacteria come in through a small skin injury. How do phagocytitc cells get from an intact capillary to the site of the injury?

chem,otaxis, slither between endothlial cells

What is the major product exported from the B lymphocyte?

antibody molecules

What type of cells are the memory cells that can jump-start the response to the next exposure to an antigen?

B lymphocytes

What kind of protein is the antigen receptor on the surface of a B lymphocyte?

antibody (IgD)

What is the difference between an epitope and an antigen?

epitope (antigenic determinant) is the small portion of the antigen to which the antibody binds

How can an infant be immune to some diseases between birth and weaning?

IgG across placenta, IgA in milk

How would a blood count help to determine if you had a systemic bacterial infection?

There are more neutrophils in bacterial infection

Explain what agglutination is using transfusion of type A blood into a type B recipient as your example.

Antibodies would cause red blood cells to clump together

How can your immune system (conceivably) develop antibodies to every possible epitope?

The genes themselves get spliced to make the many variable regions

Class 2 MHC on the surface of an antigen-presenting macrophage acts in conjunction with (what?) on the surface of a helper T cell to activate it.

CD4

Why did AIDS, in the first few years, create a new "selection pressure" against hemophiliacs?

before AIDS, the "environment" was one where clotting factor was available through medical technology; after AIDS (before the blood banks were better secured) this factor from multiple blood donors had a grim chance of being infected

What does a phagocytic cell do to destroy a bacterium after it has "swalled" it?

presumably the endosome with the bacterium fuses with a primary lysosome, though some bacteria have evolved tricks to escape the endosome

"Monocytes have a late chemotaxis." Explain: either (1) later than what? Or (2) just what do are they doing that is called chemotaxis?

1-neutrophils, 2-slither out between endothelial cells

In what way do different antibodies create different risks for the fetus, comparing the ABO blood groups vs. Rh factor.

IgM not cross placenta but IgG does so 2nd Rh+ fetus is a problem for an Rh- mother unless she has antibodies after the first is born

"Clone" is a term applied in the discussion of the development of plasma and memory cells from B lymphocytes. What is that term meant to imply?

tha after a B cell is subjected to a particular epitope, a bunch of plasma and memory cells responsive to that epitope will form

To what fraction or portion of an antigen does an antibody bind?

epitope, 5 to 15 amino acids (also groups attached to them) near eachother

Address an infant's immunity answering either (1) what kind of antibody gave the newborn some of the mother's immunities at the moment of birth, OR (2) what kind of antibody from the mother can prolong the infant's immunity (that the mother had developed) for some time after that?

(1) IgG, (2) IgA

Address allergies with either (1) what kind of antibody is released from a plasma cell, (2) to activate what kind of receptor on the surface of a mast cell, OR (3) to release what substance from a mast cell.

(1) IgE (2) IgE receptor (3) histamine

CD8 coreceptor on a killer T cell acts in conjunction with (what?) on the surface of an infected cell to destroy that cell.

Class 1 MHC (also viral antigen)


this page was last revised 7/28/09

** The somatic sensory and motor systems

Sensory and motor systems

Text: selections from Chapters 8 & 10

Personal reflection

Though broadly trained, my Ph.D. and my first job (Assistant Professor) were in psychology. It was only in 1979 that I moved to biology. Long ago, I learned of certain brain studies after transecting the spinal cord in animals: the encephale isole, French for the isolated brain. This is much like the preparatioon the Nobelist Sherrington used for studies of spinal reflexes. I came to view studies above the transection as psychology and below as physiology. Thus, to me, the somatosensory system and the motor systems seem more in the jurisdiction of a physiology course than special senses such as vision & audition.

Review

Fig. 8.28
Spinal cord has white matter (myelinated tracts)
and
Gray matter (cells and synapses)
Dorsal root ganglion has cells for sensory input
Ventral root has output (motor) axons
Unit of behavior is reflex
In addition,
Sensory information goes to brain
and
Motor output comes from brain
and that is what this outline is about

SENSORY

Touch (somesthesis) and motor representations in the cerebral cortex

Fig. 8.6
"This is your brain. This (colorful diagram) is your brain in BL A260 class"
Brain, central sulcus with post-central gyrus (somatosensory projection)
and pre-central gyrus (motor area)
Many other aspects of "localization of function" for cerebral cortex are shown here:
auditory area, visual area, Broca's area (speech)
Note also the cerebellum, an area devoted to motor coordination.

General and historical

A very compelling sense, from the pain of a tooth ache to the ecstasy of an orgasm
There has been an emphasis on submodalities (qualities such as pain vs. hot), where modalities refers to different senses like vision and audition
von Frey (around 1900) - punctate sensitivity - touch forearm with pencil, sometimes feels cold, sometimes feel pressure.
This approach overemphasized correlation of histoloogical receptor type with sensory experience.
It fit in well with Muller's (mid-1800's) "doctrine of specific nerve energies" - in which, if the ears were made to feed in through the optic nerve, sounds would be experienced as visual sensations because the quality comes from the nervous system not the physics of the stimulus.

The present view of receptors and axons depends more on nerve type and adaptation, and the central projection (axon type [A myelinated, C unmyelinated] pathway [dorsal columns = lemniscal vs anterolateral = spinothalamic) is critical.

Receptors in the skin

Fig. 10.4
Cutaneous receptors
The different types of receptors (in general, free nerve endings and encapsulated):

Free nerve endings
for pain, temperature and crude touch

Pacinian corpuscle - rapid adaptation
Lowenstein - peel to show layers make rapid adaptation
very sensitive, very large receptive field (area which, if stimulated, will affect the receptor [or higher order sensory nerve]
vibration - 250 - 300 Hz

here is a Pacinian corpuscle from our histology course

Meisner's corpuscles are fast but not as fast as Pacinian
encapsulation is with Schwann cell layers
most common receptors of fingers, palms and soles
smaller receptive field
"feeling" - active touch - would use fast as finger moves across
textured surface

Merkel's disks are slow and have a small receptive field and are for light touch
finger tips, lips and genitals
static discrimination of shape

Not in diagram

Ruffini slow - large receptive field -
sensitive to stretching in deep skin, ligaments and tendons

Krauss in lips and genitals (dry vs mucous skin)

warm and cold
a person can feel a difference of 0.01oC
relation to body temperature
(cold have additional peak at high temp - paradoxical cold -
pins and needles)
cold related to menthol
hot related to capsaicin

Nociceptors
some mediators of pain are in sting venoms
Also tissue damage substances: serotonin (platelets), prostaglandins, leucotrienes, histamine from mast cells, substance P , bradykinin from blood borne precursor
enzyme from injury, receptor is chemoreceptor
nociceptors are in many places, but not in brain, hence brain surgery under local anesthesia used im mapping studies in humans by Penfield

Spinal cord

Fig. 8.24
input into spinal cord
(does not include face & head which enter via cranial nerves [trigeminal])

LEFT SIDE OF FIGURE
Lemnicsal system is for localized touch.
Lower limbs are handled medially in fasciculus gracilis.
Upper limbs are lateral in fasciculus cuneatus.
ipsilateral projection
First nucleus is in lower medulla
There is a cross-over, medial lemniscus and then the next nucleus is in the thalamus.

In projection to the brain, there is processing - lateral inhibition to sharpen spatial localization
If you tap your forearm, there are big waves but you feel localized touch.

RIGHT SIDE OF FIGURE
spinothalamic for pain and temperature
with synapse and decussation at entry point.
There are separate tracts in spinal cord.
The lateral portion is for pain and temperature.
The ventral (anterior) part is for gross tactile sense.
Hence the nomenclature "anterolateral."
Touch can inhibit inhibit pain (a hard touch to a door knob makes an electric shock less annoying)

A half spinal cord injury would cause contralateral loss of spinothalamic below injury and ipailateral loss of lemniscal.
Brown-Sequard syndrome include motor (ipsilateral impairment)

referred pain for viscera is interseting
notably, blatter stretch receptors localize pain to genitals
heart attack in neck and left arm

Brain

TRANSPARENCY (from intro book)
Just to show you that the material in your next transparency can also be found in the freshman biology book.

Fig. 8.7

RIGHT SIDE OF FIGURE
sensory magnifications
Penfield - homunculus

MOTOR

Motor systems

LEFT SIDE OF FIGURE
topographic map of motor cortex- compare with corresponding sensory homumculus
work by neurosurgeon Penfield, note relative "magnifications"
toes (thought to curl with sexual excitement) in motor cortex across from genital projection in postcentral gyrus.)

Fig. 8.25
Pyramidal system with corticospinal tract
Corticospinal tract Pyramidal motor system (75-90% crosses) 10 to the 6th axons
named because it goes through pyramids on ventral medulla
(though it might have been named from pyramidal shaped neurons in layer V incl. Betz cells)
lateral and anterior pathways
Initiation of voluntary motor movements

output for face and upper body via facial nerve (and trigeminal, vagus, accessory, hypoglossal)

Basal ganglia (nuclei)

Fig. 8.11
Not just motor cortex, but huge parts of cortex feed to basal ganglia (and cerebellum).
Extrapyramidal (because it lies outside the pyramids)
caudate + putamen = striatum (striated because strands of internal capsule make it look striated)
putamen + globus pallidus = lentiform nucleus [lens shaped] (see sheep brain horizontal section)

Fig. 8.21
inputs to basal nuclei
substantia nigra (nigrostriatal dopamine system)
(also in medial forebrain bundle [through lateral hypothalamus] is the mesolimbic dopamine system.)

outputs from basal ganglia
The globus pallidus is a relay nucleus for the caudate and putamen and so is the subthalamus.
To VA/VL complex of thalamus to motor cortex

Disorders

Parkinson's see synapse lecture

Huntington's (1872) disease (chorea) choreoathetosis
Dominant late onset - many interesting genetic counseling issues. The Folk singer Woodie Guthrie died of Huntingtons. There is a big family tree derived from Venezuela near lake Maracaibo
On post-mortem, degeneration of putamen and caudate is observed.
It is on short arm of chromosome 4
1983 and since: cloning -CAG repeat (polyglutamine repeat), 15-34 (normal) -> 42-66 (Huntington's)
Other trinucleotide repeat diseases: fragile X syndrome, myotonic dystrophy, and others
sometimes they get worse from generation to generation (anticipation)
in some ways, Huntingtons is the opposite of Parkinsons in that circuit has thalamus increasing excitation to cortex.

Cerebellum

Dysmetria (cannot approach target), ataxia, intentional tremor if cerebellar damage
cerebellum highly developed in electric fish
cerebellum is involved in rhythmic activity and plasticity
An additional decussation makes it so that cerebellum controls the ipsilateral side of the body.

Questions from 2004 - 2008 exams that relate to this outline

Basal nuclei (caudate, putamen, and globus pallidus), part of the extrapyramidal motor system, output through the thalamus to where?

the precentral gyrus

Faciculus cuneatus and fasciculus gracilis are part of what system?

lemniscal (for fine touch)

The gene (or gene product) of the gene that is abnormal in Huntington's chorea has a variable number of what?

CAG (glutamine)

Where is the decussation (cross over) of the lemniscal system for localized touch?

in medulla

A cell in the precentral gyrus whose axon is part of the corticospinal tract makes its first synapse on what cell?

spinal motor neuron

What is the function of the postcentral gyrus?

primary somatosensory projection

What is mediated by the spinothalamic (anterolateral) system that decussates at the level it enters the dorsal root?

pain and temperature

What are cells in the dorsal root ganglion used for?

somatosensory input to spinal cord

What property do the layers of encapsulation of a Pacinian corpuscle confer?

rapid adaptation

Between the tract called the medial lemniscus and the postcentral gyrus, there is a synapse in what famous "relay station?"

thalamus

"The left half of the brain is for the right side of the body and vice-versa." Is this conventional wisdom true for pain and temperature as well as for fine touch?

yes, both, though crossings are at different levels

What is the function of the precentral gyrus?

voluntary motor initiation, motor cortex

Why is the anterolateral system so named (where is it?) and what is it used for?

location between anteriot (ventral) and lateral in spinal cord white matter, pain and temperature

Why is Huntington's disease sometimes called "chorea?"

chorea refers to jerky movements

Relate the expressions "triplet repeat" and "polyglutamine."

extra CAG's (nucleotide sequence) code for a string of glutamines (amino acid)

Where does a cell in the precentral gyrus make its first synapse?

Spinal motor neuron

In terms of localization of function of the cerebral cortex, what is the function of the postcentral gyrus?

somatosensory projection

How would the protein product of the Huntington's disease gene compare for someone without vs. with the disease?

more glutamines (amino acids) in a row with because of CAG triplet repeat

The output of the motor cortex (precentral gyrus, pyramidal system) goes all the way to the spinal motor neuron. By contrast, where do basal nuclei (extrapyramidal system) feed to?

thalamus, motor cortex

"That area of the skin, if deformed, that affects the response of one specific Pacinian corpuscle." What is this called?

receptive field

Serotonin is a mediator for nociceptors. Name another.

prostaglandins, leukotrienes, histamine, substance P, bradykinin

The spinothalamic system for pain and temperature is also called the anterolateral system. Why (does it have this other name)?

tracts are in ventral (anterior) and lateral parts of white matter in spinal cord

Between the pain receptor and the lateral spinothalamic tract, where is the first synapse?

in dorsal horn of spinal cord gray matter

Face and hand occupy about half the map of the motor cortex (precentral gyrus). How was this map determined?

stimulate brain of awake surgery patient and see where movement is

Earlier this semester, you learned that the substantia nigra does not make enough dopamine in Parkinson's disease. How does the substantia nigra feed into the motor system?

connects to striatum in extrapyramidal motor system

Voluntary motor movements for the face go out through cranial nerves. By contrast, what tract carries motor output from the motor cortex (precentral gyrus) to the lower part of the body?

corticospinal, pyramidal

Where is the cell body for the somatosensory receptor cell?

right outside the dorsal root of the spinal cord, dorsal root ganglion

What is the function of the postcentral gyrus?

somatosensory projection

Why would it be useful to have a touch receptor that is sensitive for vibration?

for active feeling

Where is the first synapse in the lemniscal input?

in the medulla (fasciculi gracilis and cuneatus)

What does it signify that the hand is as large as the arm on the motor cortex?

magnification where motor movements are more dextrous

In comparison with the extrapyramidal system, what is corticospinal spinal tract called?

pyramidal system

Where does the globus pallidus feed to?

to thalamus to motor cortex

The dopamine system is called "nigrostrital." Give the real names of the areas for which it got this name.

substantia nigra, striatum

"Nociceptors are chemoreceptors." Explain.

chemicals at the site of injury like bradykinin stimulate them

Where is the first synapse in the anterolateral input?

right in the dorsal horn

Why would half the children of a Huntington's victim be expected to get the disease?

autosomal dominant

Huntington's disease is called a "triplet repeat disease." Triplets of what?

nucleotides

Why does a textbook have a lateral view of the cerebral cortex which has different locations colored differently?

to emphasize localization of function, for instance sensory areas for different modalities

"A rapidly adapting pressure receptor is useful for active touch." Explain.

As you feel a textured surface, that receptor is vibrated

For the anterolateral system, a cell in the dorsal horn of the gray matter of the spinal cord makes its synapse (where in the brain?).

thalamus

(Refer to the previous question.) "This anterolateral system ultimately projects to the same part of the cerebral cortex as another system. Answer either (1) What is this part of the cortex called? Or (2) What is this other system? (name, location in spinal cord, OR function will suffice).

(1) motor cortex = precentral gyrus (2) lemniscal carried in dorsal columns mediating fine touch

"The corticospinal tract is for voluntary motor output." What about the face?

Cranial nerve 5 trigeminal

"Huntington's disease shows 'anticipation,' getting worse from generation to generation." What changes (molecularly)?

Nucleotide triplet CAG (that codes for glutamine

WHY (note, I am just asking why) would a half spinal cord lesion affect senses mediated by spinothalamic vs lemniscal systems below the injury differently?

Where they cross over is different, spinothalamic below the lesion, lemniscal above

62. How was the map of the postcentral gyrus obtained?

Gently electrically stimulate and ask the person where (s)he feels it

63. "The thalamus is a relay (more than a relay!) for sensory and motor systems." And yet the corticospinal tract went right past the thalamus without making a synapse. In what system, then does the thalamus have motor synapses?

Extrapyramidal - basal ganglia feed back to motor cortex via thalamus


this page was last revised 8/3/09

**Sensory systems

The Senses

Fox, part of Chapter 10, figure from chapter 8

General

There are 5 "special" senses
touch (somesthesis) - already covered in previous outline
taste (gustation) - next (this outline)
smell (olfaction - after taste (this outline)
hearing (audition) - a big topic, next outline
sight (vision) - a huge topic, the outline after next

Taste (Gustation)

for chemicals dissolved in water
Gustation - chemicals - Many "flavors" are smell
Hanig (1901) - preferential localization:
sweet - tip of tongue
salt - front sides of tongue
sour - back sides of tongue
bitter - back middle of tongue

On tongue:
Papillae: Circumvallate (preference for quinine), foliate, fungiform (preference for sucrose)
also receptors in epiglottis
epiglottis via nerve X (vagus), circumvallate (9 of them) via IX (glossopharyngial), others via VII (facial)

Fig. 10.7
Several types of papilla including the circumvallate papillae on the back of the tongue, shown in this picture from our histology course
Within each papilla are numerous clusters of cells called taste buds shown in this histology picture. support cells and sensory cells

Note that there are taste "blindnesses" Ptc = phenylthiocarbamide, taster is dominant and nontaster
Use taste vs. non-taste to screen for G-protein coupled receptors (M. Barinaga, Family of bitter taste receptors found, Science 287, 2133-2135, 2000)

Fig. 10.8
generally, channel or G-protein linked receptor ultimately increasing calcium somehow for synapse
note receptor does not have axon

salt - Na+ channel opens (depolarization)

sour - pH sensitive channel closes (depolarization)

sweet - G-protein linked cAMP close K+ channel - depolarize

bitter -G-protein cascade

umami (glutamate) - and amino acids, channels as well as G-protein cascade

In each case, Ca2+ involved in vesicle release

Taste Projection
(much simpler than for olfaction)
Gustatory nucleus in medulla,
there to thalamus and then to sensory cortex, overlap to touch area - postcentral gyrus
also from medulla to hypothalamus

Smell- Olfaction

There are unusual primaries like aromatic and putrid , there may be many primaries, although mixtures give a single perception confounding the ability to define primaries
Relative to other senss, receptors difficult to stimulate
Even more than with the sense of touch, olfaction is related to motivational "affect"
The sense of smell is especially important in other animals (dogs)

Fig. 10.9
Anatomy of olfactory epithelium.
Note: the receptors are neurons with axons, unlike for taste
Receptors are ciliary, with cilia in mucus

Transduction - G protein coupled receptor via adenylyl cyclase
There is a specialized olfactory alpha subunit of the G protein (Golf)
Na+ - Ca2+ channel is like that of photoreceptor in that cAMP acts as a ligand to open the channel from inside the cell
Ca2+ opens Cl- channel
there is also a pathway involving PLC and IP3, but which is otherwise similar
in the background, there is a Na+/Ca++ exchanger

G-protein coupled receptor is very variable (there may be thousands, meaning that olfactory receptors contribute predominantly to diversity of G-protein-coupled receptors) and has specific variable regions
Axel and Buck won the 2004 Nobel prize (Physiology and medicine for this contribution)

Projection
Glomeruli - > Mitral cells -> lateral olfactory tract

Fig. 8.15
Olfaction is a complex sensory system in part because of the CNS projection to amygdala, hypothalamus, hippocampus) , areas called Limbic system

Also

There are senses outside the 5 special senses

Vestibular sense

Fig. 10.13
note proximity with cochlea (for hearing)
utricle and sacculus linear motions
3 semicircular canals - rotations

TRANSPARENCY Fig. 10.15
stones (otoconia) provide mass for bending in utricle and sacculus

TRANSPARENCY Fig. 10.16
cupula displaced as semicircular canal fluid is displaced

transduction

TRANSPARENCY Fig. 10.14
hair cells (also for audition) [mechanoreceptor]
kinocilium (real cilium)
plus about 30 stereoocilia
mechanoreception assisted by tip links - depolarization if move toward kinocilium
hyperpolarize if in opposite direction

Test questions from 2004 - 2008 relating to this outline

What type of molecule must come in many varieties to mediate the richness of olfaction you enjoy?

G protein linked receptor

Where is the first synapse in the olfactory system?

olfactory bulb

What is detected when endolymph bends the cupula?

head rotation

What does the term "umami" refer to?

a taste, glutamate

Which sensory system projects to the limbic system, including the amygdala?

olfaction

After a bitter tastant causes Ca2+ to increase in the cell, what does that Ca2+ do?

cause transmitter release

Out of the 5 special senses, which one does not have a localized area of the cerebral cortex as its final projection?

olfaction

About how many different G protein coupled receptors are involved in human olfaction?

1000

In addition to the vestibular sense, which utilizes hair cells where "hair" refers to stereocilia?

audition

All taste cell types, by one mechanism or another, have an influx of Ca2+. What process does this increased cytoplasmic calcium mediate?

synaptic vesicle release

A portion of the brain hypothesized to be involved in olfaction, emotion, and memory.

limbic system (or any part of it)

What is PTC (phenylthiocarbamide) and what did it reveal about sensory transduction?

a substance that tastes bitter and helped in the isolation of the G protein-coupled receptor

How is the richness of olfactory experience coded in the genes for olfactory receptor molecules?

a different gene for each G protein-coupled receptor, very variable

Upon stimulation, for each taste primary, cytoplasmic Ca2+ increases. What is it used for?

for release of transmitter vesicles

The ciliary receptor cells in the nasal epithelium have axons that terminate (where)?

olfactory bulb (first cranial "nerve")

What brain center involved in motivational aspects of hunger does the olfactory bulb project to?

hypothalamus

There are three nerves that carry taste information to the brain. These three nerves are among a famous set of about a dozen that are collectively referred to as (what)?

cranial nerves

In olfactory transduction, what does cAMP do to affect the electrical properties of the receptor cell membrane?

cAMP is the ligand that gates the cation channel from inside the cell

Where are the sense organs that monitor your head position to keep your eyes upright for slight tilting of the head?

near the cochlea (for hearing)

In what way does the tastant for umami relate to a central nervous system excitatory neurotransmitter?

glutamate

About how many olfactory receptor molecules does a human have?

500-1000

In addition to G protein-coupled receptors, what is the other type of taste receptor molecule?

channel

In taste receptors, Ca2+, mediating transmitter release, comes from either outside the cell or (what subcellular structure?)?

endoplasmic reticulum

Where do olfactory neurons make their synapses?

olfactory bulb

What are the "hairs" of hair cells, and what happens when they are bent?

cilia (stereocilia), open or close channel, depolarize or hyperpolarize

In what way are calcium ions essential for the signaling of the taste receptor cells to the cranial nerves?

mediate exocytosis of vesicles

In some cases, taste receptor molecules are channels. Alternatively they are (what?).

G protein coupled receptors

Why do olfactory axons seem to zig-zag rather than just connect to the closest glomerulus? (That pertained to yellow and green receptors, as colorized in your figure, connecting to yellow and green glomeruli.)

presumably, each glomerulus receives only from receptors expressing the same receptor

In the G protein-coupled receptor cascade in the olfactory cell, how did the cAMP affect the cell's response?

ligand close K+ channel

Describe the receptor cells of the vestibular system with respect to their (1) structure, or (2) the type of stimulus that excites them.

(1) "hair" cells with stereocilia, mechanical

On the back of the tongue, taste buds are found on what larger structure (hint, nine of them, and the nerve projects by the IX cranial nerve, the glossopharyngeal).

Circumvallate papillae

65. In terms of the respective molecular biology of transduction, why is olfaction a much richer sense than taste in humans?

There are maybe a thousand receptors for different primaries


this page was last updated 8/3/09

**The audition lecture

Audition

Fox, part of Chapter 10 and one figure in chapter 8

Physics of Sound

(not all of this is in the book)
Intensity dB = 20 log (pressure 1/pressure2)
standard is 0.0002 dynes/cm2
Threshold amplitude of vibration is 10 to the -11 m (10 pico meters)

waves of compressions and rarefactions of air (must have medium) described by sine wave
Frequency Hz cycles per sec
vibration - 20 - 20,000 Hz, above which is ultrasound .
Audibility curve - Intensity [dB] vs log (freq) [Hz] very sensitive

Ear

Fig. 10.18
Ear structure
pinna, eardrum=tympanic membrane, ossicles, cochlea, part of nerve VIII = cochlear nerve

Fig. 10.19
hammer, anvil, stirrup=malleus, incus, stapes - to match impedance of air -> fluid
Eustachian tube
oval window is "inner ear drum"
20:1 "amplification" tympanic to oval

Fig. 10.20
Since the cochlea is wound like a snail, a section through it shows repeated structures

Fig. 10.22
higher magnification, most importantly basilar and tectorial membrane
also inner hair cells and outer hair cells

Auditory transduction

hair cells on basilar and tectorial membranes
3,500 inner hair cells
many more outer hair cells
Bend as basilar membrane vibrates relative to tectorial membrane

(repeated from vestibular apparatus lecture)
kinocilium (real cilium, missing in post-natal human hair cells)
plus about 30 stereoocilia
mechanoreception assisted by tip links - depolarization if move toward kinocilium
hyperpolarize if in opposite direction
Threshold displacement is about 0.3 nm

go back to Fig. 10.20
perilymph is fluid of scala vestibuli and scala tympani is like CSF - bathes baso-lateral hair cell
High K+ in endolymph of scala media (bathing hairs)
stria vascularis (endothelium lining scala media) pumps ions to produce this unusual extracellular fluid
thus when channels open, K+ comes into cell
endocochlear potential endolymph 80 mV more + than perilymph

Frequency discrimination

At about 1000 Hz, you can tell the difference of a few Hz. This is explained by Helmholtz's place theory as modified by lateral inhibition as described in Bekesy's (1961) Nobel Prize winning work on "physical mechanism of stimulation within the coclea."

At low frequencies, frequency discrimination is better explained by Rutherford's telephone theory. Here, frequencies to both ears can cause neural impulses that stay true to the frequency so that beats can be from neural comparison from the two ears.

Fig. 10.21
Vibration of basilar membrane is mapped by tonotopy
fluid vibration at oval window through helicotrema
Low frequencies vibrate mostly near helicotrema
High frequencies vibrate mostly near oval window
But the localization is crude
Lateral nhibition refines localization on the way to brain so that cells in brain respond to only a few frequencies

Fig. 10.25
Frequency map on cortex

Frequency discrimination at low frequencies
there was another theory, Rutherford's "telephone" theory
phase-locking gives volley principle up to 4 kHz

Projection

Auditory nerve to dorsal and ventral cochlear nucleus - no crossing
Several synapses on the way to the Thalamus

Fig. 10.24
Thalamus to auditory cortex

Auditory localization

difference in time of arrival and intensity (in big headed animals) [human 700 micro sceond difference]
(speed of sound 1087 ft (331 m) / s in air)
Localization up and down does not rely on 2 ears,may relate to pinna
small-headed animals are extraordinary

Exam questions fron 2004 - 2008 that apply to this outline

Helmholtz's place theory for frequency discrimination refers to place on what membrane?

basilar

Because the perilymph cannot be compressed, pressure applied at the oval window is released where?

round window

If the pressure is 0.002 dynes/cm2, 10 times the standard for audition (0.0002 dynes/cm2), how many dB is the sound?

20

The stapes drives vibrations to what structure?

oval window

If two audio oscillators set to about 1000, playing through loud speakers, give 5 beats per second, what would you perceive if you heard one then the other sequentially?

you would hear distinctly different pitches

In addition to the vestibular sense, which utilizes hair cells where "hair" refers to stereocilia?

audition

For people, in addition to intensity of sound for one ear vs the other, what contributes to auditory localization?

time of arrival

What does "tonotopic" refer to with respect to organization of the cortical projection for hearing?

different frequencies project to different places in an organized way

A log unit is an order of magnitude, i.e. 10 x. How many dB per log unit?

20

Tip links between stereocilia contribute to channels responsible for what kind of stimulation?

mechanosensation, or hearing, possibly K+

If a certain sound is 20 dB louder than another sound, how many times as loud is it?

10 x (one log unit)

Why is it reasonable to propose that a sound might arrive at the two human ears at different times?

speed of sound is finite (slow) and head is big

Why was it useful to hold the tuning fork and loud speaker to one ear simultaneously before demonstrating frequency discrimination by holding them to one ear sequentially?

beats prove that two stimuli differ by only a few Hz

"Hairs" on hair cells bend when the basilar membrane moves with respect to what other membrane?

tectorial

A young human can hear frequencies from about 20 Hz up to about (what)?

20,000

In what way is K+ particularly relevant to auditory transduction?

K+-rich extracellular endolymph in scala media (secreted by stria vascularis) makes it so that, when channels open, K+ comes into cells

Helmholtz proposed that different frequencies stimulated different places along the basilar membrane. In what way(s) was his place theory confirmed or contradicted?

true, but localization is crude, lateral inhibition corrects for this

The vestibular apparatus shares a nerve to the brain with what special sense?

auditory

"There is tonotopic localization in the auditory cortex." Explain.

different frequencies at different locations in an order

"The audibility curve extends from about 20 to 20,000 Hz." What would be the most obvious difference (from this statement) among the people in the room where your physiology course was taught.

your professor would have an age related loss at higher frequencies

Why is the round window useful, in fact necessary?

to release pressures applied to oval window since fluid cannot be compressed

What is compared that would allow you to tell which side of your head a sound is coming from?

inputs from the two ears

How is it that K+ moves in, rather than out, through channels in auditory hair cells?

an unusual extracellular fluid (endolymph) is high in K+

About how many Hz is the just noticeable difference at 1000 Hz?

2

Twenty times the log of one pressure divided by 0.0002 dynes/cm2 tells us what property of sound?

intensity

There is a cut-off of (what? - give number and units) between "sound" (that humans can hear) and ultrasound (such as dogs and bats can hear).

20,000 Hz

"Helmholtz was correct in general but wrong in the details" (about frequency discrimination). How so?

Bekesy demonstrated that different freqencies stimulated different places, but more crudely than Helmholtz imagined. (need latreral inhibition to process)

The sound may arrive at one ear 700 microseconds before the other ear. Answer either (1) How can this be? Or (2) Why is that useful?

(sound has a finite (slow) speed considering the size of the head

Movement of the organ of Corti relative to (what adjacent membrane?) causes the "cilia" of auditory hair cells to bend.

tectorial

K+ comes in through the auditory cell channel. Now, wait a doggone minute. How did that happen?

b/c K+ is high, which is unusual, in the extracellular fluid (endolymph)


this page was last revised 8/3/09

**The vision outline

Eye and Vision

Fox, a substantial part of Chapter 10

Review

Vision is usually covered everywhere, and Freeman has the topic
TRANSPARENCY (intro book) eye and retina structure
TRANSPARENCY (intro book) spectrum and spectra for the 3 cones that mediate color vision

Eye structure

Fig. 10.27
the eye picture of an ophthalmologist's office
cornea, iris, pupil, conjunctiva, sclera, extraocular muscles
lens, aqueous (anterior chamber), vitreous (vitreous chamber), retina, fovea, optic n.
there is a blind spot where the optic nerve exits

Fig. 10.31
Here is a picture showing focus of an arrow up-side-down on the retina, trivial except that is shows that most of the bending is at the cornea where the change of index of refraction at the air-cornea interface is very large.

Refractive Disorders

Fig. 10.35
refractive errors
diopters - reciprocal of focal distance in m
cornea is 0.024 m, 42 diopters
Emmetropia-normal,
Hyperopia-far-sighted, need convex lens,
Myopia-near-sighted, need concave lens, involves abnormal elongation of the eye
visual angle, acuity - Snellen eye chart - 20/20 is seeing letter 5 min (1/60 degree)

Accomodation and presbyopia

Fig. 10.34
Accomodation
loss of accomodation with age explains Presbyopia
Benjamin Franklin developed bifocals
This is a difficult concept and the best figure I've seen to explain it:
If ciliary muscle is relaxed, ligaments are tight and lens is stretched flat
If ciliary muscle contracts, ligaments have slack and lens relaxes to greater bulge for near vision.

Here, in an albino rabbit eye dissection, you can see the suspensory ligaments of the ciliary muscle.

Other disorders:

Glaucoma - pressure is too high because aqueous humor does not drain well, ganglion cells die, treated with drops or surgery
Floaters in vitreous especially in myopia
Diabetic retinopathy blood vessels overgrow, leak, blast holes in retina with laser decreases angiogenesis
Cataract - lens becomes opaque, remove and often replace with intraocular lens, made of polymethyl methacrylate, known to be tolerated since pieces from airplane visors would nlodge in pilots under fire (and since about 1988, these have been doped with UV blockers)
Retinitis pigmentosa is tragic, people can see when young, lose rod vision (tunnel vision [ring scotoma] because rods are in mid-periphery).
Rods go first and eventually cones which is strange if rod molecules are mutant.
There are autosomal and X-linked types, dominant and recessive.
There are other genetic degenerations and stationary (not progressive) blindnesses are in molecules of transduction cascade (book only mentions missense mutations in opsin) as well as in other rod and cone molecules.
There is a web site where information relevant to the retina, especially genetic causes of blindness, accumulates (site)
Age related macular degeneration may have an genetic basis too

Pupil

Fig. 10.28
An interesting and related story has to do with dilation of the pupil.
Recall that atropine, a muscarinic antagonist, dilates the pupil.
That means that the parasympathetic nervous system constricts the pupil.
Recall that parasympathetic = cranio-sacral, and here the cranial nerve is the occulomotor nerve (#III)
By contrast, the sympathetic n.s. dilates (in dim light), and the nerve has to come up from the superior cervical ganglion (of the thoraco-lumbar system)
A bright light in one eye causes the other pupil to constrict too. (Try this in front of a mirror with a flashlight.)
Neurologists can make use of information based on defects in the pupillary reflex.

Eye structure

Fig. 10.30
"the eye is the window to the brain" -- physician can actually look at CNS
For instance, increased crainial pressure (like from tumor) shows up as papilledema
Optic disc is where optic nerve exits and blood supply enters and exits.
Fovea is high acuity cone vision.
Macula lutea is area where carotenoids (lutein and zeaxanthin) form blue-blocking (yellow) filter.

Here is a picture a friend (Lynette Feeney-Burns) gave me before she retired (in about 1990). It is labeled "normal macular pigment - chow diet," and it demonstrates the density of yellow pigment around the fovea in (presumably) monkeys fed a diet adequate in carotenoids. Currently, it is known that the carotenoids lutein and zeaxanthin are in nerve layers in the light path to the receptors of the fovea (cones). We get these yellow-appearing caroteinois in our diet (e.g. from spinach and corn). It is thought that they help to protect cones from damage that may be induced by blue light. It was found that the concentration is increased with dietary increases, and now lutein is included in multi-vitamins.

Here, in a sheep eye dissection, you can see the optic disc. Retina is white, pigment epithelium and choroid are black.

Rods and Cones

TRANSPARENCY (here is a pdf of this transparency)
Hecht, Schlaar and Pirenne (1942) published a study that a human subject can see a light so dim that 6-14 quanta were absorbed over a 500 rod area; that means one rod can "see" one quantum.
Here are some calculations showing how to determine the energy of a photon using Planck's constant (obviously very low).
I also roughly calculate to show that the threshold for audition is comparably low.

Fig. 10.44
Photoreceptors- 125 million receptors 20/1 rods to cones
(converge on 1 million ganglion cells)
Adds to sensitivity of rods and to acuity for cones.

Retinal circuitry

Fig. 10.36
Retina is mounted backwards relative to the path of light
expands on the above figure with retinal wiring diagram:
Straight through: Photoreceptor -> bipolar -> "ganglion" cells (whose axons form the optic nerve)
Horizontal interactions: Horizontal cells and amacrine cells
Pigment epithelium - melanin, vitamin A conversions, and phagocytosis of spent photoreceptor membrane

rods concentrated off-fovea, cones on-fovea
Rod, peripheral vision, dim black and white, sensitive - "scotopic"
Very sensitive - 1 photon
Cone, fovea, color, acuity - "photopic"
Shown in rats, rods are supported by retinal pigment epithelium
RPE: (1) melanin that blocks light reflection
(2) metabolism to provide 11-cis retinal (chromophore ofvisual pigment, rhodopsin)
(3) phagocytosis and recycling of shed rod tips
Cells are postmitotic and the indigestible residue of the phagolysosomal system is lipofuscin, a fluorescent aging pigment, a topic on which I've done research.

Color vision

Fig. 10.42
spectral sensitivity of rods and 3 cone types
confirms Young -Helmholtz trichromatic theory
3 kinds of cone 420 530 560
3 kinds of cone opsins which are evolutionarily related in humans and OW monkeys
green and yellow (middle and long wavelength) cone opsins are near each other on X
(blue cone opsin is on human chromosome 7, rod on chromosome 3)
evolutionary bottleneck hypothesis color vision re-evolves after nocturnal life (where adaptive pressure for cone vision is relaxed) early in mammalian evolution
Red or green color blindness - on X, thus preferentially in males.
Blindnesses were thought to be from altered genes, but numbr of copies in human population is variable, and cross-over accidents can even make chimeric genes.
Female "carriers" should actually be mosaics of color blind vs normal retina because of Mary Lyon X-inactivation hypothesis
superfamily of G-protein-coupled receptors (7 transmembrane domain receptors)

Phototransduction

Fig. 10.39
light causes 11-cis retinal (aldehyde of vitamin A, retinol) to turn to all-trans.
("retinene" - term used in book - is old fashioned)
George Wald 1967 Nobel prize

Fig. 10.40
The alpha subunit of transducin (the name for the G protein) activates cGMP PDE (phosphodiesterase)
Less cGMP (ligand) and channel closes so cell hyperpolarizes since sodium channel closes.

Fig. 10.41
This figure repeats the above point.
Because there are Na+ channels in the outer segment and a Na+-K+ ATPase in the inner segment (where there are lots of mitochondria manufacturing ATP), there is a dark current turned off in the light.
(Also shows how rod cell is a stack of disks with rhodopsin and other transduction molecules)
Transmitter is released in dark - but less when light is on

Wiring

(and processing - my coverage here will be minimal)

10.45
Temporal retina does not cross at optic chiasm but goes to ipsilateral lateral geniculate nucleus (part of the thalamus)
Nasal retina goes to contralateral LGN
At LGN, inputs from 2 eyes does not mix.
Projection to cortex where eye inputs mix for stereopsis, and processing for contrast, moving lines, angles, etc takes place.
Superior colliculus (important for eye movement control)

My interests center around vision, so a visit to the research interests of my home page will offer various topics about vitamin A, ultraviolet light, and Drosophila mutants. The Biology Department has a vertebrate vision specialist, Judith Ogilvie. Dr. Ariel in SLU's Pharmacology Physiology Department is one of my fellow wizards in visual science.

Exam questions from 2004 - 2008 relating to this outline


What intracellular ligand, whose function is to open channels, is decreased when light stimulates a rod?

cGMP

Energy equals Planck's constant times the frequency. Energy of what?

of one photon

For what population of people is macular degeneration most common?

elderly

What must be bound to the G-protein-coupled-receptor protein to make the fully-functional rhodopsin molecule that absorbs light?

retinal

What happens to a rod's neurotransmitter release when light hits the rod?

decreases

The ciliary muscle contracts, in accomodation, to let you do what?

see up close

How does an eye care professional test for glaucoma?

poke the eye for a pressure check

In the dark, a current of Na+ ions flows from the sodium pump in the inner segment through what in the outer segment?

channels

When an axon from a ganglion cell goes toward the brain in the optic nerve, where does it first synapse?

thalamus

What layer at the back of the eye is black?

retinal pigment epithelium, also choroid

Some men taking Viagra (sildenafil) report impaired color vision. Why might this be?

Viagra and phototransduction both involve cGMP

Where are the genes of the long- and middle-wavelength cone rhodopsins located?

X chromosome

Our gaze seems more relaxed for far vision even though suspensory ligaments are relaxed for the lens to accomodate for near work. What does contract to change the lens shape to see up close?

ciliary muscle

A current of Na+ in the dark along the rod is from the Na+/K+ pump in the inner segment and what in the outer segment?

Na+ channel (or transduction machinery)

What specific cellular defect explains the tunnel vision (ring scotoma) of retinitis pigmentosa?

rods degenerate

What is the only direct effect of light in initiating phototransduction?

cis -> trans isomerization of retinal

What kind of lens corrects for myopia (near-sightedness)?

concave

Which two rhodopsins used for human color vision are coded by adjacent genes on the X chromosome?

middle and long wavelength (green and red [yellow])

Ganglion cells are killed from high eye pressure. What is this disorder called?

glaucoma

What layer of black cells supports rod outer segments by phagocytosis and conversions of vitamin A?

retinal pigment epithelium

Epinephrine binds one G protein-coupled receptor (GPCR). What other GPCR, used for vision, is a pigment that contains a form of vitamin A?

rhodopsin

As it applies to diabetic retinopathy, what is angiogenesis?

formation of new, fragile, blood vessels

Laser photocoagulation decreases angiogenesis. Here we are treating to prevent further blindness from what disorder?

diabetes

Which side of the retina projects to the ipsilateral lateral geniculate body at the optic chiasm?

temporal

Macular degeneration (MD) aflicts a certain population as reflected by the "A" in the name (AMD). What population?

elderly (A=age-related)

Under what conditions are cGMP levels in the rod lowered?

when stimulated by light

Why is it inaccurate to consider a chromosomally normal woman to be be a carrier for a recessive X-linked color blindness if the other chromosome is normal (wild-type, dominant)?

mosaic of cells with one vs the other X functioning (Mary Lyon X inactivation hypothesis)

Why does each eye have a blind spot?

there can be no receptors where the optic nerve exits

Why is cataract usually a less severe form of blindness than retinitis pigmentosa?

there is straightforward surgery for cataract, whereas rods die and cannot be recovered for rp

Scientific information has led to the decades-old conventional wisdom that vitamin A is good for vision. Other than being the pigmented portion of rhodopsin, where else do carotenoids come in to play, explaining why lutein is a dietary supplement or a component in a multi-vitamin pill?

macular pigments protect fovea from blue light

Presbyopia is a defect in what process that affects most people over 40 years old.

accomodation

Why is the cornea actually a stronger lens in the eye than the lens?

because of the big change in index of refraction from the air-cornea interface

Why is the rod depolarized in the dark (but not in the light)?

because cGMP opens sodium channels

The genes for the yellow- and green-light absorbing rhodopsins are near each other on which chromosome?

X

The tip of the rod outer segment is sloughed off on a daily basis and "recycled." Where does this cellular fragment go?

into retinal pigment epithelium

What does activation of the parasympathetic portion of the occulomotor nerve do to the pupil?

closes

If your eye pressure is high, answer ONE of the following: (1) name of disorder, (2) what is not draining appropriately, or (3) loss of what cells mediates vision loss?

glaucoma, aqueous humor, ganglion cells

How can rhodopsin be mutant yet the patient still can see until retinitis pigmentosa first presents in the teens or 20's?

in autosomal dominant, a normal recessive gene still expresses rhodopsin

Suppose you could stimulate a nerve to achieve the same effect as applying belladonna alkaloids to the eye. What type of nerve would you stimulate?

sympathetic

A whole lot of rods converge onto each ganglion cell. What does this wiring achieve?

sensitivity

What is lost in age related macular degeneration (AMD)? (Your answer can be cellular or functional.)

cones, fovea; vision

If you stare straight at a mark (X), while a stimulus is presented to both eyes to the right of the X, describe how the stimulus projects to the thalamus (lateral beniculate nucleus).

temporal retina of left eye - ipsilateral projection; and nasal retina of right (contralateral) to left

In the molecular mechanism from light absorption to hyperpolarization of the rod, exactly what does 11-cis retinal do?

absorb light, convert to trans

Why would you see much better under water with vs without goggles?

keep the normal air-cornea interface (with the normal indices of refraction)

"The blind spot is about 15o off fovea in your nasal retinal field (temporal visual field)." Translate.

location off axis is measured in angle, since the optic nerve exits 15o on the side toward the nose, the inversion of the image would make it seem 15o off to the side

"Visual experience can influence the progression of myopia." On what basis can that statement be made with scientific authority?

research where the vision was distorted with goggles and the eye changed

"If the ciliary muscle is relaxed, the ligaments are tight and" Finish this thought with respect to the shape of the lens and what that does for vision.

lens flattens for distance vision

In the course a lifetime, a retinal pigment epithelial cell's ability to carry out it's function might deteriorate. Why?

it fills with the indigestibloe residue of the phagolysosomal system

If you were convinced that blue light damages foveal cones, how might you alter your diet starting now, while you are young, to delay age related macular degeneration (AMD)?

eat veggies or vitamin pills with lutein or zeaxanthin

With what sort of methodology were scientists as early as 1942 able to come to the conclusion that a rod can respond to one photon?

psychophysics, human subjects report if they can see calibrated lights

"A derivative of vitamin A is the chromophore of rhodopsin." Translate.

vitamin A aldehyde is the light absorbing portion attached to the protein

Why would the evolution of red-green color vision on the X chromosome relate to the richness of olfactory sensation?

it is a simple example of the evolution of G protein-coupled receptors

"Color normal is dominant, color blind is recessive, hence women can be heterozygous carriers for green blindness." Why is this an oversimplification?

they would be mosaics of cells with one or the other X functioning

Why is there an extracellular current from the rod outer segment to its inner segment in the dark?

The channel letting Na+ in is in the OS, the sodium pump is in the IS

In terms of the channel gating, why does a rod hyperpolarize in response to light?

the ligand (cGMP) that holds the Na+ channel open is broken down

You stare at an X with your right eye. Answer either (1) Where would the blind spot be? (state this using the sort of terminology that might be used in optometry) Or (2) How would you determine where it is while you are staring at the X?

a certain angle (about 15 degrees) off axis (away from the fovea) in the temporal visual field (nasal retinal field)

A muscle that mediates accommodation contracts. Answer either (1) What happens for your vision? Or (2) What happens to the shape of the lens?

(1) better for near vision (2) becomes rounder

"The loss of vision is referred to as a 'ring scotoma.'" Answer (1) What disorder? Or (2) Why is it a ring?

1-retinitis pigmentosa, rods (in mid-periphery) are lost

Which portions of the nervous system mediate constriction and dilation of the pupil?

parasympathetic (constriction) and sympathetic (dilation)

One photon absorbed by rhodopsin elicits an electrophysiological response in a rod. That plus what retinal wiring consideration makes scotopic vision tremendously sensitive?

convergence of multiple rods to one ganglion cell

Why does the retinal pigment epithelial cell have so much to phagocytose?

tips of outer segments are shed daily

How (between New World monkeys and Old World monkeys) did there get to be (at least) two color vision genes on the X chromosome?

unequal crossing over duplicated the gene

What is the only thing that light does directly to excite rhodopsin?

cause 11-cis to all trans isomerization of retinal

A light is switched on. What happens to the transmitter release from the rod?

decreased

The eye pressure is high. Answer either (1) What isn't draining properly? (2) Death of what cell type would mediate vision loss? Or (3) What is this condition called?

Aqueous humor, ganglion cell, glaucoma

Why would a person with my interests need to use Planck's constant?

Since it gives energy of a photon, it can assist in calculations of light intensity

When an ophthalmologist looks at your retina, what is the second most conspicuous landmark after the optic disc?

Macula (fovea)

What does the Mary Lyon X inactivation hypothesis have to say about heterozygous carriers of red or green colorblindness (both of which are on the X)?

It should not be a matter of dominant vs recessive, but her retina must be a mosaic

What is it that allows the sodium channel in the rod outer segment close?

Removal of cGMP by phosphodiesterase

In the visual projection, where is the first place where inputs from both eyes can connect to the same cell?

Not until the cortex

What is lost making people with age related macular degeneration (AMD) blind?

Cone (foveal) vision

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this page was last revised 8/3/09