**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

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this page was last updated 7/1/09