**The first lecture
Introductory lecture
Reading assignment: Chapter 1 and other material specifically referenced
What is life?
Fig. 3.1
showing a cell
If this were the first lecture for introductory biology, we would ask,
"What is unique to life?" and we might argue that "Inside the
cell is alive. Outside is not. The plasma membrane is thus the gate-keeper that
separates the quick from the dead."(1) Then we would develop the following
list:
#1. Life is very complex.
#2. Life has excitability.
#3. Life has development.
#4. Life utilizes metabolism.
#5. Life's processes are regulated by homeostasis
#6. Evolution is major unifying principle
#7. Reproduction is fundamental
In introductory biology (but not in physiology), we would concentrate on:
#1. Life is very complex and has complex macromolecules (DNA, RNA, protein).
#3. Life has development, growth, form
#6. Evolution is major unifying principle, and present-day organisms have an
unbroken ancestry of 3 1/2 billion yrs
#7. Reproduction is fundamental causing us to define "survival" in
biology in terms of reproduction and production of fertile offspring.
What is Physiology?
In Physiology, we will concentrate on:
#2. Life has excitability, movement and responsiveness (irritability,
sensitivity)
Figure
Excitability - Copy of a page
from a mathematically oriented text from 1971 text (2)
In the mid-1800's, it might be hard to distinguish a physiologist and a
physicist, and Helmholtz made contributions in both disciplines.
Figure
Nervous system -Copy of a page
from the book I used when I took physiology in 1969 (3), by Sir Bernard
Katz, (Nobel Prize, 1970), one of many neuroscientists to win the Nobel Prize in Physiology and
Medicine
#4. Life utilizes metabolism, and we will concentrate on:
Catabolic processes, for the production and delivery of energy. (However, we
will not dwell on the bioenergetics coverage as much as "BL A302 Cellular
Biochemistry and Molecular Biology.")
and
(to a lesser extent) Anabolic processes, involving build-up. (You have heard
the term "anabolic steroids," such as testosterone and drugs of abuse
among athletes.)
Perhaps, foremost, in Physiology, we will concentrate on
#5. Life's processes are regulated by homeostasis
Homeostasis: the thermostat
TRANSPARENCY (Review figure from introductory biology) A fundamental example is
the thermostat.
Negative feedback is sometimes referred to as a servo mechanism.
The thermostat works by negative feedback.
In house, "effector" would be furnace heat
Heat (energy) is what changes temperature.
1 calorie raises temperature of 1 ml of water 1 degree C
(the "calories" you "count" in a diet are kcal's)
Importantly, it takes about 540 calories to turn 1 ml of water to vapor.
Thus, for evaporation, we lose a lot of heat by panting or sweating.
This is called "insensible" water loss, not because it does not make
sense but because you are not aware of it as you are for micturation.
Ectotherms "cold" (ambient) blooded.
Endotherms (homeotherms).
Figs. 1.3 and 1.4
"set point" 37oC
Humans - 98.6oF = 37oC
Reset thermostat's set point in fever (pyrogens).
Antipyretics (like aspirin) or hibernation lower set point.
Produce heat by shivering or increasing metabolism (with thyroxine,
epinephrine)
Decrease heat loss: Arrector pili (smooth muscle) for piloerection (fluffing
fur) , vasoconstriction (closing peripheral capillary beds).
Increase heat loss by panting [for dog] or sweating [for person] or
vasodialtion.
Homeostasis: weight regulation
One of my favorite examples of regulation is weight regulation. My fellow graduate
students and their professor in the early 1970's studied the hypothalamus, a
part of the brain you will see in a few minutes, and its involvement in weight
regulation. People actually regulate their food intake well. It is stated that
no calories are lost (in feces or urine) [except that glucose is lost in urine
of people with untreated diabetes]. Thus, you eat the same amount you need for
energy catabolism (2000-3000/day) or else you gain or lose weight. I checked
the calculations and found that 250 extra calories per day (1 cookie/day) would
result in gaining 25 lb/yr (and very few people are gaining or losing weight
that precipitously).
Levels of analysis
Levels of analysis (from introductory biology):
element - molecule - organelle - cell - tissue - organ - organ system -
organism - population - biosphere
Levels of analysis (for this human physiology course):
cell - tissue - organ - organ system - organism
Integrating body functions
To make everything function in cooperation, systems of integration are needed:
(1) hormones (examples of homeostasis, next)
(2) nervous system (first major topic of the semester)
Fig. 6.29
shows these mechanism as well as paracrine (local hormone)
In both cases, a chemical is used.
Neuron uses small amount of neurotransmitter applied directly to target
(muscle, nerve or gland)
Endocrine (ductless) gland (as opposed to exocrine gland with duct) puts a
larger amount of hormone into blood stream where it can affect one or several
target organs.
Homeostasis - hormones
TRANSPARENCY (review figure from introductory biology)
Here's the bottom middle of the brain, the hypothalamus.
Also, the pituitary to which the hypothalamus connects.
The anterior part of the pituitary puts out ACTH (adreno cortico tropic
hormone).
["AC" refers to adrenal cortex, "T "refers to trophic
effect, "H" stands for hormone.]
ACTH positively regulates the cortex of the adrenal gland (just north of the
kidney).
The adrenal cortex puts out cortisol that feeds back negatively the anterior
pituitary to decrease ACTH.
The Hypothalamus sends CRF (corticotrophin releasing factor) through the portal
vessel to the anterior pituitary for ACTH release.
[Explanation of "portal" -- Mostly, the circulatory system is
"wired" in "parallel," but for 3 systems, hypothalamus->pituitary,
intestine->liver and kidney cortex->kidney medulla, the blood flows first
to one then to the other, i.e. it is "wired" in "series".]
ACTH feeds back negatively to the hypothalamus to decrease CRF.
Fig. 11.16
[a similar example from your text]
TRH (thyrotropin-releasing hormone) (Note, "hormone" term,
"factor" above.)
TSH (thyroid stimulating hormone)
Fig. 11.3
"Thyroxine" has two forms, T3, T4, formed from dimer of tyrosine
(amino acid) with 3 or 4 iodines attached.
What everybody should know about thyroid hormone:
Fig. 11.25
Goiter insufficient dietary iodine
Fig. 11.24 TRANSPARENCY
Goiter
Figure 11.26 TRANSPARENCY
Hyperthyroid syndrome in adult
TRANSPARENCY
Cretinism hypothyroid in infant
Dietary iodine is from sea food. Now iodine is added to salt.
It is because of thyroxine that you should worry if there is a reactor leak
(like 3 mile Island or Chernobyl), and the solution is taking lots of iodine so
that any radioactive iodine you are exposed to will be competitively swamped
out for thyroid uptake.
Roger Guillemin and Andrew V. Schally won the 1977 Nobel Prize
for their discovery of these releasing hormones (factors), a heroc task because
they are present in vanishingly small amounts (because of the efficiency of
hormone delivery through the portal vessel).
References
(1) see p. 117, G. Audesirk & T. Audesirk, BIOLOGY Life on Earth (3rd ed.),
New York, Macmillan, 1993.
(2) see pp. 48-49, D. J. Aidley, The physiology of excitable cells, Cambridge,
University Press, 1971.
(3) see pp. 34-35, B. Katz, Nerve, muscle and synapse, New York, McGraw-Hill,
1966
(4) S. Freeman, Biological Science, Upper Saddle River, NJ, Prentice-Hall, 2002
Exam questions from 2004 - 2008 relevant to this lecture
Under what circumstances does a person lose calories via the urine?
untreated diabetes
What is an anabolic steroid?
a hormone like testosterone that bromotes muscle growth
Why might you take iodine supplements if you are downwind of a reactor
accident?
have more "cold" iodine to compete with radioactive iodine for T3 and
T4 incorporation
"Tropic," the "T" in "ACTH" means affecting the
activity of. Specifically, on what gland does ACTH have this trophic affect?
(i.e. What does the AC stand for?)
adrenal cortex
What does piloerection do to regulate back to the set point?
fluffing the fur prevents heat loss
Name a substance for which the portal vessel from the hypothalamus to the
pituitary is specifically "designed."
TSH, others like it
What does panting achieve for a dog?
evaporative cooling
ACTH triggers the release of what hormone from its target gland?
cortisol
Relate the statement "Aspirin is an antipyretic" to the concept of
homeostasis.
pyrogens reset the thermostat to cause fever
"Insensible" is a term applied to water loss by perspiration or
panting in contrast with the water loss by micturition. What does
"insensible" mean?
you're not aware of it
Relate the amount of energy an average adult uses per day in catabolic
metabolism to the energy needed to increase the temperature of 1 ml of water by
1 degree C.
2000 k cal / day relative to the definition of one calorie
What is the set point for the human hypothalamic thermostat in degrees C?
37
Why are sweating and panting so effective for increasing heat loss?
the heat of vaporization is 540 cal
Why is the term "anabolic" applied to steroids abused by some
athletes?
they cause build-up as oppoaed to break-down (in catabolism), in this case of
muscle mass
How does aspirin affect the set point of the thermostat?
it is antipyretic
What would be specified with the term "catabolism" in distinction
with the more general term "metabolism?"
breakdown
How does vasoconstriction decrease heat loss?
Less radiation of warmth from extremeties
Why is testosterone referred to as an "anabolic steroid?"
it favors muscle growth
If there were a deficiency of iodine in the diet, which pituitary hormone would
be produced in excess, leading to goiter?
TSH
ACTH has a negative feedback to control what hypothalamic hormone in order to
regulate its own (ACTH's) level?
ACTH
Why is it especially useful for a person to sweat when hot?
Evaporative heat loss
In terms of the human thermostat, when would shivering be a useful behavior?
Muscle activity generates heat
"You do not lose calories through your feces and urine." What is the
most notable exception to this generalization?
Untreated diabetes mellitus
Why don't most people gain or lose a lot of weight rapidly?
homeostasis - they eat the right amount
State one of the physiological mechanisms for decreasing heat loss in mammals.
piloerection, vasoconstriction
Why are some steroids are called "anabolic?"
they favor growth
"Neurotransmitters are strategic because they are so discrete and thus use
a minimum amount." Why on earth would there be hormones then?
they reach many areas
How does glucose get into the cell?
transport, facilitated and co-transport with sodium
What hormone does the adrenal release in response to ACTH?
cortisol
There is a lot less TRH than TSH. Why?
TRH delivered neatly via portal system
How is paracrine signaling distinguished from endocrine signaling?
paracrine is local
Why is panting and perspiring so effective to increase heat loss?
because of the large heat of vaporization of water
A fat is a triglyceride. How come membrane lipids have only two fatty acids in
text book diagrams? (i.e. What is the third item linked to the glycerol?)
the polar head group
"Endemic" was the term your text used for (what?) disorder of inland
people who had no seafood (in the old days)?
goiter
The lay expression for ectotherm is "cold-blooded." Why is that
inaccurate?
More like they assume ambient temperature
How come homeotherms (endotherms) always have heat available for maintaining
body temperature at the set point?
Because of inefficiency in metabolism, waste is heat
In addition to triiodothyroxine, what is the other thyroid hormone?
T4
In your homeostasis lecture, ACTH was used as an example. What keeps ACTH
levels from getting real high?
homeostasis (negative feedback from cortisol)
Adrenalin comes from the adrenal medulla. By contrast, where does ACTH exert
its trophic effect?
adrenal cortex
What is the opposite of vasodilation and what is this (the opposite of
vasodilation) useful for (in terms of homeostasis)?
vasoconstriction would decrease heat loss (body's thermostat)
A diagram from the introductory biology book showed how hypothalamic CRF
(corticotropin releasing factor) caused the anterior pituitary to secrete ACTH
(adrenocorticotropic hormone). Why is this hormone referred to as CRF?
corticotropin = ACTH, factor=hormone, causes its release
Guillemin and Schally won a Nobel Prize for for their discovery of releasing hormones
(factors), a heroic task because they are present in vanishingly small amounts.
Why can there be such small amounts of these hormones (compared with other
hormones).
portal vessel delivers it without dilution
A nuclear reactor spews out radioactivity upwind of where you live. Quick! What
should you eat to minimize thyroid damage?
nonradioactive iodine to compete with the radioactive for uptake
this page was last revised 6/10/09
**The Membrane Lecture
Membranes
Fox, Chapter 6, plus some references back to earlier and later chapters and to
Freeman
There's enough lipid to make two layers
Fig. 6.13
shows how red blood cells react to hypertonic, isotonic and hypotonic
solutions.
Get a good source of membranes:
red blood cells (erythrocytes) from adult human have only plasmalemma.
Gorter and Grendel showed in1925 that there was enough lipid to make two
layers.
Put red blood cells into distilled water, they burst from hyposmotic shock and
become only "ghosts" - membrane only.
Blood cell counts, and geometry solves for membrane surface.
Extracted lipids on a surface have an increased lateral stability when they
reach a monolayer which, when measured is twice the membrane area.
Here is a snapshot I took
of oil on a road after rain - when oil is multiple layers, you see color, and
layers slip, when oil is one layer, it is black.
Fig. 6.7
(To understand how hypotonic shock burst the erythrocyte, I introduce a
fundamental concept, osmosis)
Osmosis - water moves passively from where water is at a higher concentration
(for instance pure water) to where water is at a lower concentration (where
organic chemicals are dissolved in it)
through a semipermeable membrane (i.e. a membrane which passes water but not
the organic molecules).
Membrane structure
TRANSPARENCY (Review from an introductory text)
glucose transporter, like
Fig 6.16
shows bilayer of lipids with protein in it
Notice that the lipid molecules are drawn in this "cartoon" as a ball
with two sticks.
Most membrane lipids are phospholipids with:
(1) a polar (hydrophilic) head group
and
(2) hydrophobic fatty acid (acyl) tails
Another example allows introduction of another fundamental molecule:
TRANSPARENCY (Review from an introductory text)
Here is a famous membrane protein, rhodopsin, the molecule we see with, and how
7 hydrophobic alpha helices of the protein fit into the hydrophobic part of the
membrane (the milieu created by the fatty acid tails). For future reference,
retinal is the chromophore, the component (chromophore) that makes the protein
[proteins are otherwise not colored] into a pigment. Retinal is a derivative of
vitamin A. Rhodopsin is in the membranes of rods and cones, visual receptor
cells, shown in the diagram. Rhodopsin is the prototypical G protein-coupled
receptor (GPCR), and GPCRs are used for hormones, neurotransmitterss,
olfaction, taste and others.
Electron microscopy (EM)
Fig. 3.2, Fox
Robertson did work that led to earlier bilayer model.
He saw 2 "electron dense" (dark) lines in EM when stained osmium, an
electron dense heavy metal. Davson and Danielli developed a membrane model from
Robertson's vistas.
Fluid mosaic Singer and Nicolson the more modern version
Picture I made freeze
fracture replicas with this apparatus. Specimen is prepared, frozen to liquid
nitrogen temperature, put inside a vacuum, smashed with a razor (membranes
break down the middle between the fatty acid tails), blasted from an angle with
a platinum gun (to shadow protein with electron dense heavy metal), blasted
from above with a carbon gun (to hold replica together), then the tissue is
dissolved away.
Here, from my research, is an example
of how things look. Picture shows visual membranes in Drosophila.
High vitamin A flies have membranes full of protein (the same rhodopsin I
mentioned above) while vitamin A deprivation decreases this protein.
Membrane biochemistry
Membrane lipids are composed of:
(1) Phospholipids such as phosphatidylcholine (lecithin)
I did some research on the
phospholipids of the Drosophila head. Using radioactively lbeled phosphate,
many different phospholipids are visualized after they have been separated on a
TLC (thin layer chromatography)
plate.
(2) Cholesterol
(3) Glycolipids such as one that accumulates in Tay-Sachs, a hereditary
lysosomal storage disease,1/30 American Jews carry, recessive, fatal at 6 mo -
5 yr
Alexa B. Serfis in SLU's Chemistry
Department studies membrane lipids and their proteins
Membrane physiology
Relevant to physiology, if the membrane had only lipids, it would have
extremely high resistance. This is because the hydrophobic milieu in the center
of the membrane does not allow water, a polar solvent, or ions which carry
current. The membrane is only permeable because some of the proteins are
channels that pass ions. Also, there is high capacitance. The concepts of
resistance and capacitance will be dealt with shortly.
Membrane signalling
Lipid makes a barrier to anything polar or big like protein hormone or
epinephrine (bind receptor).
(This receptor is the GPCR, mentioned above.)
Steroid hormones can go in
It used to be thought that lipids just sit there. In the 1980's it became clear
that they turn over metabolically and that some products of membrane lipid
turnover are important mediators of intracellular signalling. This is very
fundamental and will come up repeatedly in later.
Fig. 11.9, Fox
Hormone -> receptor protein (GPCR) -> G-protein -> cascade makes
second messengers (IP3 and DAG [diacyl glycerol, not in your diagram]) from the
membrane lipid PIP2 [phosphatidylinositol-4,5-bisphosphate, not in your
diagram], note that calcium ion Ca2+) becomes a next messenger in the cascade.
Important points that will come up repeatedly:
Phospholipase C is the enzyme [and I have a research interest in PLC]
IP3 is a "ligand" for a calcium channel.
Ca2+ is sequestered inside endoplasmic reticulum.
Inside a cell's cisterns is tantamount to outside the cell.
Ca2+ is high outside and low inside, like Na+ (sodium ion) unless deliberateluy
increased intracellularly.
Ca2+ levels are so important that 3 hormones regulate blood Ca2+, parathormone,
calcitonin and vitamin D.
Membrnne channels
Fig. 7.26
Nicotinic Acetylcholine receptor [More on this later])
Acetylcholine is a ligand (neurotransmitter), nicotine is a pharmnacological
agonist.
This receptor is a channel (for ions, giving the membrane electrical
conductance [g])
Channel is ligand gated.
Sodium (Na+) and potassium (K+) shown going through pore in membrane that can
be open or closed.
Sodium, higher outside the cell, is likely to go in.
Potassium, high inside the cell is likely to go out.
The 1991
Nobel prize in physiology and medicine was awarded to prize was awarded jointly
to: ERWIN NEHER and BERT SAKMANN; they developed patch clamping that allowed
electrical recording from single channels.
In 1963
the Nobel prize was awarded jointly to: SIR JOHN CAREW ECCLES , SIR ALAN LLOYD
HODGKIN and SIR ANDREW FIELDING HUXLEY for their discoveries concerning the
ionic mechanisms involved in excitation and inhibition in the peripheral and
central portions of the nerve cell membrane; Hodgkin and Huxley worked on the
voltage gated channels of the axon's action potential and Eccles worked on the
neurotransmitter gated channels at synapses.
In summary, the topic of ion channels is pretty fundamental.
Fig. 7.21
Also holes in membranes from one cell to another are important:
Gap junctions - 2 hexamers in register of connexin protein
This is a very big channel.
Important in many places, especially connecting one heart muscle (myocardial)
cell to another electrically.
Membrane transport
Fig. 6.19
"sodium pump"
A large fraction of the cell's energy (ATP) goes to pumping ions (active
transport)
This creates an ion imbalance, sodium Na+ high outside cell, potassium K+ high
inside.
This gives rise to the membrane electrical potential (voltage) important in
nerve and muscle cells.
Fig. 3.4
bulk transport:
phagocytosis - cell eating
pinocytosis - cell drinking
Receptor mediated endocytosis - clathrin coated pits turn to vesicles, clathrin
is a protein that makes vesicles look fuzzy.
Receptor mediated endocytosis is important in clearing lipoproteins, LDL and
HDL, from blood (later), and, of course, a receptor protein in the membrane is
important in the transport.
From my research, a coated pit.
In summary,
Functions of membrane proteins
(1) transport
(2) many enzymes are on the membrane
(3) receptors for hormones, neurotransmitters and developmental signals are on
the membrane.
(4) cells are joined by proteins
(5) cells communicate by proteins
(6) cells hook to extracellular proteins by proteins
Reference:
E. Gorter and F. Grendel, On bimolecular layers of lipoids on the chromocytes
of the blood, J. Exp. Med. 41, 439-443, 1925
Exam questions from 2004 - 2008 relevant to this outline
With answers
Why do you need lead, osmium, uranium or platinum to see aspects of membrane
structure in the electron microscope?
heavy metals are electron dense
What did hypotonic shock do to what kind of cells to allow Gorter and Grendel
to show that there was enough lipid in the membrane to make two layers?
burst red blood cells to make red blood cell ghosts with a measured membrane
surface area
Why do you need a chromophore (such as retinal for rhodopsin and heme for
hemoglobin) to make a protein into a pigment?
proteins do not absorb visible light
How does a steroid hormone get into a cell?
that can pass the lipid barrier
How do sodium ions get forced out of the cell?
active transport with a protein that uses ATP
The nicotinic receptor is a cation channel for what two ions?
K+ and Na+
Rhodopsin and neurotransmitter and hormone receptors interact with what
downstrean heterotrimeric protein?
the G protein
What do you call electrical junctions from cell to cell with channels composed
of hexamers of connexin protein in register?
gap junctions
What must be bound to the G-protein-coupled-receptor protein to make the
fully-functional rhodopsin molecule that absorbs light?
retinal
As a result of phospholipase C (PLC) activation, what ion is released into the
cytoplasm from smooth endoplasmic reticulum?
Ca2+
In what fundamental way does the location of a steroid hormone receptor differ
from that of the receptor for epinephrine?
steroid receptor is in cell, epinephrine receptor is in membrane
In a "cartoon" of a membrane phospholipid, there is a ball with two
tails. The ball is the polar (hydrophilic) head group. What are the two tails?
fatty acids (acyl groups)
Which direction does the ATPase pump sodium ions?
out of the cell
Epinephrine binds one G protein-coupled receptor (GPCR). What other GPCR, used
for vision, is a pigment that contains a form of vitamin A?
rhodopsin
What is the name of the electrical connection between myocardial cells composed
of connexin proteins?
gap junction
Why does an erythrocyte turn into an erythrocyte ghost when placed into
distilled water?
because of osmosis, it swells and bursts
When a membrane lipid is drawn as a ball with two sticks in a diagram, what are
the ball and sticks respectively?
polar head group, fatty acids
One signal transduction product of phospholipase C (PLC), diacylglycerol (DAG),
is in the membrane while the other, IP3, inositol trisphosphate, goes into the
cytoplasm. Where is the precursor, PIP2 (phosphatidylinositol-4,5-bisphosphate)?
it is a membrane phospholipid
When the nicotinic acetylcholine receptor channel opens, there is an efflux of
K+. Why?
because it allows Na+ and K+, so K+ goes down its chemical gradient
One membrane protein is sometimes called the Na+-K+-ATPase. What is its
function?
pumps Na+ out, K+ in
What is the function of a hexamer of connexin proteins in one cell's membrane
in register with a similar hexamer on the adjacent cell?
gap junction connects adjacent cells' cytoplasm and passes current
How can it be that a cortisol receptor is intracellular while so many hormone
receptors, for instance for epinephrine, are on the membrane?
steroids pass through the membrane
Robertson's pioneering electron microscopy paved the way for Davson and
Danielli's bilayer membrane model and Sanger and Nicolson's fluid mosaic model.
Why were heavy metals like osmium necessary for that demonstration?
Electron dense
If water and ions are excluded from the center of the membrane, where fatty
acids reside, how is it that a G protein-coupled receptor can span the
membrane?
There are hydrophobic amino acids
Tay-Sachs disease is a fatal autosomal lysosomal storage disease. What
accumulates?
glycolipid
Before I introduced metabotropic receptors (G protein coupled proteins that
bind a ligand such as a neurotransmitter), I showed rhodopsin, the prototypical
G protein coupled receptor. Why doesn't rhodopsin need to have a ligand bind to
it? (i.e. What does it have that a neurotransmitter receptor does not have?)
it has retinal, a vitamin A derivative
Researchers have been able to make artificial membranes out of phospholipids in
a hole between two compartments in a water bath. Why would membrane lipids
naturally arrange themselves as they are aligned in membranes?
polar heads would orient to water and hydrophobic tails toward eachother
In the phosphoinositide signal cascade, phospholipase C (PLC) makes
"second messengers" IP3 (inositol trisphosphate, the polar head
group) and what(?) from the membrane lipid PIP2 (phosphatidylinositol-4,5-bisphosphate.)
[If you do not remember, I have put enough information into the question that
you should be able to figure it out.]
diacyl glycerol
Osmosis was referred to as passive transport. Is the sodium-potassium pump
passive? Justify.
no, it is active b/c it uses ATP
After feeding radioactive phosphate, extracted lipids were visualized by
audioradiography of a TLC (thin layer chromatography) plate. Why didn't I see
the sort of lipids that accumulate in Tay Sachs disease?
it is glycolipids and would not take up phosphate
If you fracture a frozen membrane, proteins are exposed. But you cannot see
them in the transmission electron microscope unless you do something. What?
you need to make a replica, shadow it from an angle with an electron dense
material (platinum)
Under what circumstances (what do you do?) does a passive process (what
process?) let you make a red blood cell ghost from a red blood cell?
Put r.b.c into distilled water, osmosis
Tell me about a famous lysosomal storage disease. Your answer can be
biochemical, cell biological, or genetic.
Tay Sachs fails to break down a glycolipid that accumulates in the cell,
autosomal recessive carried in Ashkenaze Jews
In the transmission electron microscope, what membrane specialization of
receptor mediated endocytosis is visualized?
Clathrin coated pits (vesicles)
This page was last updated 6/15/09
**The bioelectric potential lecture
Neurons
Fox Chapter 6 and 7. Note that web material is especially important for this
lecture
Figure 7.1a
typical neuron
Connections, from other neurons, created graded electrical potentials at
synapses, on dendrites and cell bodies.
Cell body integrates the synaptic excitatory and inhibitory voltages.
If there is net excitation, axon propagates the all-or-none, non -decemental
action potential quickly over long distances.
Overview
Excitable membrane has resting and action potentials
Ions are dissolved in water and are pumped using ATP -> ADP for energy,
Na+-K+-ATPase.
This "sodium pump" uses 1/3 (2/3 if high electrical activity) of cell
These ion gradients establish "batteries" as ions can flow through
channels.
Other than channels and pumps, membranes do not pass ions well (covered
before).
For resting potential, Potassium (K+) channels dominate.
For action potential, Sodium (Na+) channels open (activate) then close
(inactivate).
Toward the end, a different type of K+ channels open (activate) then close
(passively, they do not inactivate).
Action potentials are all-or-none big depolarizations.
Synaptic (graded) and sensory (generator) potentials are smaller.
They can be of variable size and can be depolarizing or hyperpolarizing.
History
1791 Luigi Galvani (Italy) (of Galvanometer fame) - nerve muscle electricity in
frog
1850 Herman von Helmholtz - speed of conduction (40 m/s)
Walther Hermann Nernst
(Germany) (1864-1941) 1920 Nobel in Chemistry.
Nernst equation says that ion gradient is equal and opposite to voltage
difference.
(often misunderstood)
1902 (paper) Julius Bernstein apply Nernst, K+ permeability lost in action
potential.
(insightful but short of the full story)
TRANSPARENCY (from R. D. Keynes, The nerve impulse and the squid, Scientific
American, December, 1958).
squid giant axons
1939 K. C. Cole and H. J. Curtis (US) introduced use of squid and showed that
membrane resistance decreases during passage of action potential
Invertebrates do not have myelin to speed the velocity of propagation of the
action potential.
Theoretically, this velocity increases with the radius, and so invertebrates
use giant axons when fast action potentials are needed.
Squid uses quick mantle contraction and jet propulsion through siphon in escape
response.
1950's Sir Alan L. Hodgkin & Sir Andrew F. Huxley (Great Britain)
1963 Nobel
Prize in Physiology and medicine for "ionic mechanisms...excitation
inhibition...nerve cell membrane"
In general, They showed what was stated above:
For action potential, Na+ channels open then close, K+ channels open (then
close)
Electrical concepts
Fig. 6.26, Fox
Sodium is high outside.
Potassium is high intracellularly.
pdf
Circuits (equivalent circuits)
Battery, anode:+, anions:-, Cathode:-, cations:+
Current = i (Amps), defined as + to - (Benjamin Franklin)
Potential (potential difference): V or E (Volts)
(1) Battery (source of electromotive force, EMF)
(2) Current flow through a resistor
battery and resistor in circuit
E = IR (Ohm's law), R in units of Ohms, W
G is conductance, 1/R, "mho" = Siemens (S)
I = gV
delay in depolarizing or hyperpolarizing membrane
Membrane capacitance
Thus, this is a low (frequency) pass (high cut-off) filter
Typically, capacitance adds delays
There are also high pass filters
Derivation of Nernst potential
Fig. 6.26, Fox (again)
Because of the potassium gradient there is a resting potential of about -65-70
mV
pdf
Assume two compartments in communication
(ions like K+ or Na+ dissolved in each)
Free energy (of each system) = RT ln Ci + ziFF
chemical electrical
F is absolute potential, C is concentration, i is given ion, e.g. K+ or Na+
T is tempreature in degrees Kelvin
R = 8.31 Joules/moleoK
F = 9.65 x 104 Coulombs/mole
[ = 6.02 x 1023 ions/mole x 1.6 x 10-19 Coulombs/ion ]
Assume equilibrium which means
(1) no flux
(2) electrical and chemical gradients equal and opposite
(3) energies of two compartments the same
Simple algebra and the fact that log10 = 2.3 x ln gives:
EK+ = 58 log [K+]out / [K+]in
K+ in 140, K+ out 5
Na+ in 5-15, Na+ out 145
Fig. 6.27
Because of the potassium gradient there is a resting potential of about -65-70
mV
(like before but with voltmeter drawn in
Goldman equation
pdf
There is an equation that looks like the Nernst equation except that is has
sodium (Na+), potassium (K+) and chloride (Cl-) and their relative
permeabilities. Permeabilities change as a function of time.
David Goldman, 1943
assume constant field, this derivation is "beyond the scope of this
course" (way too dificult)
Vm = 58 log PK[K+]out + PNa[Na+]out + PCl[Cl-]in
PK[K+]in + PNa[Na+]in + PCl[Cl-]out
(see pdf for equation drawn more neatly)
Note that in and out are reversed for Cl- since it is an anion while Na+ and K+
are cations.
There is a membrane model with 3 batteries (note that the sodium and potassium
batteries are reversed because the gradients of these two cations are
opposite).
The relative permeabilities are modelled by variable resistors (potentiometers)
[where variable conductances, the inverse of resistances, are more analogous to
variable permeabilities]
Wheatstone bridge
How to determine an unknown resistor
Use two knowns as voltage divider
use a variable and the unknown as another voltage divider
Use a galvanometer as a null detector between the two nodes
Cole and Curtis used an AC bridge to show that resistance decreased during the
action potential
Kirchoff's laws
Such a membrane model seems to suggest a confusing circuitry, simplified by
several simple concepts.
Kirchoff's first law: at any junction, sum of currents is zero.
Kirchoff's second law: sum of changes in potential around loop is zero.
There is a pdf to
illustrate a problem and its solution using Kirchoff's laws.
The solution involves 3 equations with 3 unknowns (high school algebra)
[or determinants, slightly more advanced high school algebra].
Reference
R. D. Keynes, The nerve impulse and the squid, Scientific American, December,
1958
Exam questions from 2004 - 2008 relating to this outline
Write an equation obeying Ohm's law relating voltage and current but using
conductance rather than resistance.
if E=IR (Ohm's law), then E=(1/g)I, so I=GE
What is assumed in the derivation of the Nernst equation?
energy of two compartments is the same which is tantamount to saying that
electrical and chemical gradients are equal but opposite
What two components are used in the circuits of high- and low-pass filters to
give them the property of having a time constant?
R & C
Permeability to what ion increases at the beginning of the action potential?
sodium
Write an equation expressing conductance as a function of resistance.
G=1/R
Faraday's constant (9.65 x 104 Coulombs/mole) is important in expressing
electrical component of energy of a thermodynamic system. What do you need to
multiply the charge of an individual ion (1.6 x 10-19 Coulombs/ion) by to get
Faraday's constant?
Avagadro's number (the number of ions per mole)
What is the name and polarity of the electrode to which cations would migrate
in solution?
cathode is negative
After the nerve cell integrates the excitatory and inhibitory post-synaptic
potentials, which part of the cell propagates the action potential (if
threshold is reached)?
axon
If I graphed Ohm's law with Voltage on the Y axis and current on the X axis, I
would get a line. What is the slope?
R
Invertebrates do not have myelin. What adaptation allows for fast action
potentials in invertebrates?
giant axons
What type of impedance makes it so that Voltage would change as a function of
time?
capicitance
What is the expression commonly used to describe an action potential and to
differentiate it from a graded synaptic potential?
all-or-none
What is the term for the inverse of resistance, an electrical term analogous to
relative permeability?
conductance, g
There are two components of energy in a thermodynamic system. Which component
is RT times the log of the concentration?
chemical energy
Both resistance and capacitance are membrane impedances. In what way is
capacitance distinguished from resistance?
Voltage across capacitor changes as a function of time
The squid does not have myelin. How does the squid have fast action potentials?
Giant axons
Around 1900, Bernstein explained the action potential by a loss of the
selective K+ permeability during the action potential. Although insightful,
this was two bricks shy of a load. What, in fact, changes and in what
direction.
Na+ permeability goes up (depending on how you read "what direction,"
inward flow)
Voltage can arise from a battery and (what else)?
current flowing through a resistor
How does the capacitance of the axon compare with that of the axon membrane
plus the myelin?
many membrane layers, each with capacitance, add reciprocally, hence the answer
is "lower with myelin"
People do not have giant axons while squids do. How do we achieve, in our
axons, what squids do with that adaptation (giant axons)?
myelin
What happened to axon resistance when Cole and Curtis used the AC Wheatstone
bridge as the action potential was passing?
went down
When batteries and resistances for sodium and potassium are drawn to model the
Goldman equation, what special properties do the resistors have to account for
the resting and action potentials?
must be variable (potentiometers)
How do Schwann cells vs oligodendrocytes differ with respect to investing axons
with myelin?
Schwann, one axon, oligo a few
During propagation of the action potential, what depolarized the axon to
threshold at any given location?
the action potential at one place triggers
A deliberate slight of hand had me graphing Ohm's law with the X and Y axes
reversed. Thus, we talked about "conductance" which relates to what
way of describing how well ions traverse a membrane channel?
permeability
Why might a middle-aged person who had recovered partially from "infantile
paralysis" (polio) experience a relapse?
Post polio syndrome has sprouts of motor neurons going away (motor unit goes
back to before recovery of function)
In terms of understanding resting, graded and action potentials, what does the
Goldman equation (and its equivalent circuit) convey that the Nernst equation
does not?
it takes into account several ions and their relative permeabilities
Applying the equilibrium assumption in deriving the Nernst equqtion (both
thermodynamic systems have the same energy) we show that the electrical
potential difference (across the membrane) is equal and opposite to (what?)?
chemical gradient
A current is injected into a membrane to change the membrane's voltage. How
does the membrane capacitance change the membrane voltage?
it causes delay (as the membrane capacitance charges)
A deliberate slight of hand had me graphing Ohm's law with the X and Y axes
reversed. In this "I-V curve" what is the slope of this line?
conductance (g)
Why do squids have giant axons? Your answer can be behavioral, it can pertain
to the properties of giant axons, or it can be comparative (comparing squid
with "higher" nervous systems).
so they can contract their mantle for the escape response synchronously, giant
axons conduct faster, invertebrates do not have myelin
Why is salutatory conduction so much faster than conduction without myelin?
all that insulation forces the action potential to jump way ahead to the next
node of Ranvier
Why is the prefix "oligo" applicable to olidodendrocytes?
they myelinate several axons in the CNS
"Capacitors in series add reciprocally." What does this say about the
capacitance of myelin?
less current would leak out of the axon through the membrane capacitance where
there is myelin
Why do squids have giant axons? Your answer can be behavioral, it can pertain
to the properties of giant axons, or it can be comparative (comparing squid
with "higher" nervous systems).
so they can contract their mantle for the escape response synchronously, giant
axons conduct faster, invertebrates do not have myelin
Why is salutatory conduction so much faster than conduction without myelin?
all that insulation forces the action potential to jump way ahead to the next
node of Ranvier
Why is the prefix "oligo" applicable to olidodendrocytes?
they myelinate several axons in the CNS
"Capacitors in series add reciprocally." What does this say about the
capacitance of myelin?
less current would leak out of the axon through the membrane capacitance where
there is myelin
By passive spread, a spike at one place depolarizes the axon ahead of it (and
behind it) to threshold. Why is conduction unidirectional?
because the sodium channels behind it are inactivated, causing the absolute refractory
period
Why might a middle-aged person who had recovered partially from "infantile
paralysis" (polio) experience a relapse?
Post polio syndrome has sprouts of motor neurons going away (motor unit goes
back to before recovery of function)
An oscilloscope presents the action potential like a graph. What are on the X
and Y axes?
X time, Y voltage
Why was Golgi's technique, so exquisitely used by Ramon y Cajal, a contribution
worthy of the Nobel Prize?
Among a zillion cells, one cell could be seen in its entirety
This page was last updated on June 16, 2009
**The action potential lecture
Action Potentials
Fox, Chapter 7 (mostly)
Spike propagates nondecrimentally long distances
Fig 7.4
Typical nerve
Most important information - axon is relatively long.
There are various shapes.
Top - this looks likes the input to the spinal, the cell is in the dorsal root
ganglion
Middle - there are bipolar neurons in the retina
Bottom - this looks like the spinal motor neuron, cell in ventral horn of
spinal cord gray matter.
In this multipolar neuron, synapses are on dendrites and cell body, axon
carries action potential
Fig. 7.11
oscilloscope
essentially graphs voltage as a function of time
The figure introduces the terms depolarization and hyperpolarization
Properties of the action potential
Fig. 7.13
(What everybody should remember about the action potential based on the
background you are assumed to have.)
At threshold, Na+ channels open (then close), and Na+ diffuses in
After peak of action potential (spike), K+ channels open, and K+ diffuses out
The spike is all-or-none, as opposed to having variable sizes like synaptic
potentials or receptor potentials.
After the spike, there is a refractory period (when another spike cannot be
started), and this insures unidirectional propagation.
Note that the depolarization to threshold shows the membrane acting as a low
pass filter.
Fig. 7.19
Spike depolarises the axon ahead of it to depolarize the membrane to threshold
Passive propagation
Introduction. "Action" potential refers to the active voltage-gating
that opens the Na+ channel that allows nondecremental propagation. If that did
not happen, propagation would be decremental based on the passive spread of
current going down the axon and also leaking out the membrane.
Fig. 7.19
(look back, I already showed it)
Current going down axoplasm and leaking out membrane
The recorded potential gets smaller
pdf
Cable equation
Summary:
(1) an action potential at one place depolarizes the membrane ahead of it to
threshold.
(2) the spread is passive.
(3) current down the axoplasm leaks out through membrane resistance and
capacitance.
(4) solving, space constant varies with square root of radius, time constant
independent of radius.
(5) that is why invertebrates use giant axons for fast propagation.
Myelin speeds up the action potential
Fig. 7.7
Transmission electron micrograph (TEM) of myelin.
Membrane is wrapped around and cytoplasm is squeezed out, leaving only
alternating bands of electron density and lucency at high magnification.
Each layer of membrane has high resistance, and resistors in series block
current flow through membrane.
Each layer of membrae has high capacitance which would leak current, but
capacitors in series add reciprocally, decreasing capacitance and leakage.
Fig. 7.20
Myelinated axons have faster propagation.
Invertebrates do not have myelin, and that is why they have giant axons.
Here's why: action potential jumps from one node of Ranvier to next,
"saltatory" (leaping) conduction
Myelin is invested by different cells in peripheral vs central
nervous systems
Fig. 7.6
In PNS (peripheral nervous system), myelin is made from multiple membrane
wrappings of Schwann cell.
One axon
Disrupted in polio (poliomyelitis)
Polio (poliomyelitis) is a viral disease that damages myelin in peripheral
nervous system causing paralysis; then the nerve cell degenerates.
Salk (1955, injected) then Sabin (eat sugar cube) vaccines in the 1950s, before
that, only passive immunity from gamma globulin from people who had polio.
Serious cases required an iron lung.
FDR had polio.
Neuron's trophic effect on muscle is seen as muscle (not directly diseased)
deteriorates.
Recent literature
It is thought that there is some recovery where motor neurons branch more (they
already branch to innervate all of the muscle cells [fibers] of one motor unit)
so that surviving neurons
innervate muscle cells "abandoned" by lost nerve cells.
But at middle age, there is increased fatigue, pain and weakness (post-polio
syndrome).
Cause: those sprouts are lost.
L.S. Halstead Post -polio syndrome, Scientific American, April 1998 42-47
Fig. 7.8
In CNS (central nervous system), myelin is formed from oligodendrocytes.
Multiple axons, hence the prefix "oligo" (a few).
Disrupted in multiple sclerosis.
Multiple sclerosis (MS) (Anette Funicello, Montell Williams, Richard Prior,
"the president" in West Wing) damages myelin in the central nervous
system
Might aflict motor function, vision, or others
Hits people 20-40, with deterioration but sometimes episodic, i.e. with
remissions
Animal model - EAE (experimental allergic [autoimmune] encephalitis) to myelin
basic protein.
Such a disorder used to happen with rabies vaccination when virus was gron in
brain (before it was grown in eggs).
Hodgkin Huxley Nobel
experiments
Fig. 7.14
resting potential is based on predominant K+ permeability
then Na+ channels activate
then Na+ channels inactivate
then a late K+ channel activates
Channels
GENERALIZATION - action potential is based on Na+ and K+
there are MANY other channel types
Fig. 7.12
inactivation is "stopper" on chain
Tetrodotoxin puffer fish (saxitoxin dinoflagellates) block Na+ channel
Questions from 2004 - 2008 that relate to this outline
You apply a depolarization (below threshold for triggering an action potential)
at a certain place along the axon. Why would it get smaller the further away
from this place that you
record?
because current leaks out through the membrane
What is a disease of central nervous system myelin?
multiple sclerosis
What electrical properties of myelin contribute to saltatory conduction?
R & C
Permeability to what ion increases at the beginning of the action potential?
sodium
According to cable equation calculations, how does the speed of propagation
relate to the radius of the axon?
square root of radius
Describe a difference between an oligodendrocyte and a Schwann cell.
myelinate several vs one axon, also CNS vs PNS
After the nerve cell integrates the excitatory and inhibitory post-synaptic
potentials, which part of the cell propagates the action potential (if
threshold is reached)?
axon
Invertebrates do not have myelin. What adaptation allows for fast action
potentials in invertebrates?
giant axons
If current from a depolarizing stimulus travels down the axoplasm, how come the
recorded voltage would get smaller with increasing distance from the stimulus
(according to the passive, "cable" properties)?
because current leaks out through membrane resistance and capacitance
What property keeps the action potential from triggering an action potential
behind it as it travels down the axon?
refractory period
How does the capacitance of the multiple layers of membrane in myelin compare
with the the capacitance of one layer of membrane of an axon?
capacitance in series adds inversely, so, fortunately, multiple layers have less
Why is the muscle smaller when it is innervated by a nerve damaged by polio?
because the nerve has a trophic effect on the muscle
What happens to the size of the action potential as you go along the axon?
it is all-or-none, always the same
What does "oligo-" in "oligodendroglia" refer to?
a few, each glial cell myelinates a few axons
Conductance to what ion activates late in the action potential?
The late conductance increase is for K+
If multiple sclerosis involves an immune attack on myelin basic protein, and if
everybody has this protein in their myelin, how come everybody does not have
MS?
rarely does autoimmunity develop
Suppose a cell's resting membrane potential is -60 mV (inside negative). Give a
reasonable value for the potential if it received an inhibitory synaptic input
causing a graded hyperpolarization.
-65
Explain why propagation of the action potential is unidirectional in terms of
the refractory period.
spike cannot triger a spike behind it because that membrane is still not excitable
From the cable equation, we derive properties of the space constant and the
time constant. How does that tell us why invertebrates have giant axons?
space constant increases with the square root of the radius
Given that current leaks through capacitors and that membranes have high
capacitance, how come myelin, with its many membrane layers does not leak a
huge amount of current?
capacitors add reciprocally
For multiple sclerosis, explain autoimmunity (i.e. distinguish it from active
immunity against antigens in pathogens).
the antigen is probably a myelin protein
There are cells that look like pseudomonopolar neurons in the dorsal root
ganglion (just outside the spinal cord). What function do these cells serve?
sensory input
If you had one size of axon, why would the depolarization 1 mm ahead of a spike
be greater with myelin than without (assuming the Schwann cell's myelin is 1 mm
long).
Myelin's resistance and capacitance decreases current loss across that distance
What is the toxin from puffer fish that blocks the Na+ channel (and hence the
action potential)?
tetrodotoxin
What happens with botulism toxin? (Your answer can be molecular, cellular, or
physiological.)
cleave synaptobrevin, block vesicle release, muscles blocked
The conclusion from Loewi's work was that there must be a substance involved.
How did his classic experiment show this?
juice from chamber where vagus stimulation slowed heart slows heart in another
chamber
Describe the geometry of the input to the spinal cord of the muscle stretch
receptor.
cell body is in ganglion as axon goes into dorsal root
If ms (multiple sclerosis) can arise from exposure to myelin basic protein, how
come everyone does not have ms?
proteins sequestered from imune surveillance except when there is autoimune
disease
Why do they call neurotransmitter vesicles in the process of release
"omega figures?
in EM they look like the Greek letter
Ionotropic vs. metatotropic is a way to distinguish neurotransmitter receptors.
If muscarinic is metabotropic, what is the corresponding ionotropic receptor
for cholinergic transmission?
nicotinic
What is the immediate precursor for dopamine and why is it especially useful as
a treatment for patients?
l-DOPA can be given to Parkinson's patients because it crosses the blood brain
barrier
What binds to adenylate cyclase to activate so that it makes cAMP out of ATP?
alpha subunit of heterotrimeric G protein
What does protein kinase A (PKA = A kinase) do to the proteins it affects?
phosphorylates them
Once it is activated, what keeps the alpha subunit of the heterotrimeric G
protein from running amuck and continuing to activate the next molecule in line
in the cascade?
it has GTPase activity then recombines with beta gamma
Where (specifically) is synaptobrevin and what (molecularly) does botulinum
toxin do to it?
on vesicle, cleaves (prevents vesicle release)
Reuptake is the predominant mechanism to terminate norepinephrine action. By
contrast, how is acetylcholine action ended?
breakdown by AChE
Why might an inhibitor of monamine oxidase (MAO) relieve depression?
potentiate "upper" action of norepinephrine by keeping it around
Why do squids have giant axons? Your answer can be behavioral, it can pertain
to the properties of giant axons, or it can be comparative (comparing squid
with "higher" nervous systems).
so they can contract their mantle for the escape response synchronously, giant
axons conduct faster, invertebrates do not have myelin
Why is salutatory conduction so much faster than conduction without myelin?
all that insulation forces the action potential to jump way ahead to the next
node of Ranvier
Why is the prefix "oligo" applicable to olidodendrocytes?
they myelinate several axons in the CNS
"Capacitors in series add reciprocally." What does this say about the
capacitance of myelin?
less current would leak out of the axon through the membrane capacitance where
there is myelin
By passive spread, a spike at one place depolarizes the axon ahead of it (and
behind it) to threshold. Why is conduction unidirectional?
because the sodium channels behind it are inactivated, causing the absolute
refractory period
Why might a middle-aged person who had recovered partially from "infantile
paralysis" (polio) experience a relapse?
Post polio syndrome has sprouts of motor neurons going away (motor unit goes
back to before recovery of function)
An oscilloscope presents the action potential like a graph. What are on the X
and Y axes?
X time, Y voltage
Why was Golgi's technique, so exquisitely used by Ramon y Cajal, a contribution
worthy of the Nobel Prize?
Among a zillion cells, one cell could be seen in its entirety
this page was last revised 6/17/09
**The muscle lecture
MUSCLE
Fox Chapter 12 (plus references to chapters 5, 7 & 15)
How muscle works molecularly has been a real success story in cell-molecular
biology.
Cell structure
Fig. 12.1
Skeletal ("striated" = striped) muscle cell ("fiber" =
cell) 10- 100 microns [micro, 10 to the minus 6. meters] (huge) and long (from
tendon to tendon)
There are smaller units within fiber called "myofibrils" (1-2 microns
in cross section)
Thus 1000-2000 myofibrils/fiber
Fig. 12.6a&b
Sarcomeres are units along the length of myofibrils
Interestingly, the striped (striated) pattern of myofibrils is in register for
all the myofibrils in the fiber giving the whole muscle fiber a striated
appearance.
Within the myofibrils are the filaments
Actin - G (globular) polymerizes to F (filamentous) actin - the thin filament
Myosin - (2 heavy chains and 4 light chains) - the thick filament
I-band (isotropic - light), A-band (anisotropic, dark) based on actin and
myosin, see figure
here is a picture
from our histology course,
but watch out because the arrows for A, I, and H do not point accurately
Muscle proteins
Fig. 12.8 like last figure
Z disc where actins are joined in the middle of the actins
M line in the middle of the myosin
A (anisotropic)= where myosin is
I (isotropic) where actin is but not myosin
H (helle) (lighter) where there is myosin but not actin
This figure shows titin a gigantic protein that is elastic
"Clinical application" box on p. 356
Muscular dystrophy (Duchenne) X-linked recessive (sex-linked), affects boys
Lethal by age 20
"Dystrophin" protein associated with muscle cell membrane, binding
cytoskeleton with extracellular matrix.
Sliding filaments
AFHuxley & RNiedergerke, 1954, Nature
173 971-973
Interference microscopy of living muscle fibers
HHuxley & J Hanson, 1954, Nature 173
973-976 (back to back!)
Changes in the cross-striations of muscle during contraction and stretch and
their structural interpretation
Contraction of muscle was well-described in 1958 (H.E.Huxley, The contraction
of muscle, Scientific American, Nov. 1958); he is not related to the other
Huxleys, Thomas (zoologist and advocate of Darwin), Thomas's grandson,
biologist Julian, Julian's brother Aldous, author of Brave new world,
and Julian's and Aldous's half brother, Nobelist Andrew F.
Huxley whose other work
(with Hodgkin) we covered earlier.
Fig. 12.9a&b
Sliding filament explanation of muscle contraction
Fig. 12.21
The length tension curve shows that the optimum is when there is good overlap
without the actin colliding (note, there will be an important difference for
heart muscle.)
Involvement of ATP
Fig. 12.10
picture myosin as a boat rowing through a sea of surrounding actin molecules.
Fig. 12.12
Interestingly ATP binding unhooks myosin from actin. This can be remembered by
thinking about rigor mortis (box p. 348) - a "stiff" in a detective
show - has been dead long enough so that ATP has run out and actin and myosin
are locked together. ATP -> ADP and a phosphate added to the myosin and this
is like the rower back-stroking to get ready to take another power stroke. When
the phosphate gets kicked off of the myosin, the myosin and actin bind,
followed by the power stroke
Involvement of Ca2+
Fig. 12.14
Ca2+ ions are released to make muscle contract (explained later)
tropomyosin on actin
troponin has a Ca2+ binding site like calmodulin
Ca2+ binding to troponin pulls tropomyosin off of actin's binding sites for
myosin
The neuromuscular junction
Fig. 12.3
here is a similar picture
from our histology course
of the neuromuscular junction
Action potential from nerve opens channels (nicotinic acetylcholine receptors)
at "synapse" called the neuromuscular junction. (Notice that the
nerve branches.)
This is a big "synapse" and it works.
Here is a transmission electron micrograph of a portion of a neuromuscular junction. Note
the folds, increasing the area on the muscle cell. Note the space with electron
density in the cleft. Note the numerous vesicles.
Bernard Katz shared the 1970 Nobel prize
for using the quantal nature of transmission at the neuromuscular junction. The
quanta are individual vesicles. The neuromuscular junction is like any synapse
except bigger and easier to study. This information could fit equally well
here, in the muscle lecture, or in the synapse lecture (but that was already
crowded with Nobelists.
Box in Chapter 7 on page 184
Table 15.10
autoimmune diseases
Myasthenia gravis is an autoimmune attack on nicotinic receptors
Muscle weakness
Here's a picture
I found on the web of the eyelid droop
Give AChE (neostigmine) inhibitor neostigmine to ameliorate symptoms
Table 7.5
nicotine is an agonist. there are pharmacological antagonists (curare, a plant
alkaloid from Clondodendron tomentosum)
Important for mechanisms of muscular relaxatants used in surgery (like
succinylcholine)
Must relax muscles in surgery but must prove that anesthesia is adequate.
The spinal motor neuron
Clinical applications Box on p. 380
Amyotropic Lateral Sclerosis (Lou Gehrig's disease affects spinal motor
neurons)
some cases familial led to identification on chromosome 21
coper/zinc Super Oxide Dismutase (SOD1) reduces oxygen radicals
some famous baseball personalities, Lou Gehrig set consecutive
games record until broken by Cal Ripken Jr.
Lou Gehrig's farewell
speech
Fig. 12.4
(relative to the aforementioned "nerve branches") Motor units
(how many muscle cells per motor neuron)13 eye, 1730 calf
The muscle cell's action potential
Fig. 12.16
Then action potential goes down muscle cell. But cell is too big. So transverse
tubules (T tubules) get action potential into cell at numerous locations (for
each sarcomere and for each myofibril). Proximity with a specialized smooth
endoplasmic reticulum called the sarcoplasmic reticulum causes release of Ca2+.
That "proximity" involves actual interaction of the types of Ca2+
channels in transverse tubules and in sarcoplasmic reticulum.
Fig. 12.19
1 - 1 spike, tetanus for sustained
Note that eventually, fatigue sets in.
A few years ago, in General physiology lab, one of the lab groups obtained the
result shown Here. the
result when tetanus was obtained by increasing the amplitude of stimulation.
In summary:
ACh to synapse Ecxitation to spike
Final common pathway - motor neuron carries integrated information from nervous
system
action potential in membrane and t-tubules, t=transverse
Ca++ release from sarcoplasmic reticulum (ER)
T at A-I junction in Skeletal muscle but it is at the z line in cardiac muscle
and in frog skeletal muscle
Types of skeletal muscle:
Difference obvious in turkeys
Fast twitch, strong, anaerobic, white meat
Slow twitch, enduring, aerobic, dark meat
capillaries (hemoglobin), myoglobin, cytochromes in mitochondria
can alter with training
It is possible to stain, in this case for ATPase, to show mixed muscle cells in a
muscle (dark is slow, aerobic).
Metabolism:
Fig. 12.24
phosphocreatine (creatine phosphate [backup, battery]) makes ATP using
phosphpcreatine kinase
Fig. 12.22
muscle uses glucose and fatty acids (from plasma)
and glycogen and triglyceride (from muscle)
Glycogen -> (glycogenolysis) -> glucose
Overall, 1 glucose can give up to 38 ATP's, a few from glycolysis and the rest
from the mitochondrion
Without oxygen, make ethanol (yeast) or lactate (lactic acid).
Anaerobic glycolysis is used to deliver ATP quickly but wastefully (squandering
glucose).
Make ATP's but need to regenerate NAD+ [from NADH] to make.
Fig. 5.6
Lactic acid contributes to fatigue in muscle and oxygen debt, and the liver
eventually reconverts.
Anaerobic cellular "respiration" is needed in times of extreme exertion
because the heart (cardiac output) is the limiting factor in delivery of oxygen
to muscle.
Lactic acid is also made by bacteria in yogurt, sour cream, and cheese.
Fig. 16.37
Hemoglobin off-loads oxygen to myoglobin
Monitoring muscle stretch
Fig. 12.27b
remember reflex from synapse
lecture
knee-jerk reflex - tap patellar ligament, spindle (stretch receptor, alpha
motoneuron to muscle)
gamma motor neuron goes to nuclear chain fibers (intrafusal muscle) to set tone
on spindle
sensory fiber wraps around nuclear bag fiber
Smooth muscle
In an undergraduate physiology lab, a piece of rabbit gut is connected to a
force transducer. Rhythmic contractions are monitored. Drugs
like atropine (see autonomic
lecture) slow motility, and this is why it is in anti-diarhea medications. When
I was a kid, a teaspoon of some terrible tasting stuff called paregoric cured a
belly ache right away, but you can't get paregoric (tincture of opium) any
more.
Fig. 12.35 b & c
smooth muscle - arterioles, gut, uterus - involontary, autonomic
actin and myosin are arranged differently (striations helped in sliding
filament theory)
Fig. 12.36
Ca2+ comes across cell membrane, not from SR
activates myosin light chain kinase, phosphorylation
phosphorylation (and dephosphorylation) of myosin regulates cross-bridge
Fig. 12.37
regulated by autonomic neurons with varicosities and synapses enpassant
in single unit, autonomic activates then it passes from cell to cell
in multiunit, need to activate each cell
Dr. Fisher is our muscle expert,
and he teaches a course in exercize physiology
Exam questions from 2004 - 2008 related to this outline
Shortage of what chemical leads to rigor mortis?
ATP
What is an intrafusal motor fiber?
presets stretch on spindle's stretch receptor
What does a kinase do to a protein?
phosphorylates it
Suppose you are stimulating the nerve to the gastrocnemius muscle. What would
BoTox do to the response?
decrease it
When does a spinal motor neuron cause a hyperpolarization at the end plate of a
striated muscle cell?
never
In the middle of the dark A band is a lighter H zone. Why is it lighter?
because there is myosin but no actin
What ion, critical to muscle contraction, binds troponin, pulling tropomyosin
myosin's binding site on actin?
Ca2+
What is the ATP binding protein in muscle?
Myosin
During exercise, what does the conversion of phosphocreatine to creatine
achieve?
makes ATP
During anaerobic metabolism in muscle, what is pyruvic acid converted to?
lactic acid
The sarcoplasmic reticulum calcium release channel is closely related with what
channel on the transverse tubule?
a different calcium channel
Several diagrams in your book referred to skeletal muscle fibers as
"extrafusal muscle fibers." Why?
to distinguish them from intrafusal in muscle spindle
What happens to the relationship of actin and myosin when ATP binds?
they unbind
While exploring the Amazon, you are shot with a blow-gun dart of curare. What
would that do to you?
paralyze
For the monosynaptic knee-jerk reflex, what cell does the sensory neuron of the
spindle's stretch receptor synapse onto?
spinal motor neuron
Why is Duchenne muscular dystrophy more common in boys than in girls?
because the mutation is X-linked
What does "striated" mean in the context of striated muscle, and why
was the fact that muscle is striated important in developing the sliding
filament theory?
striped, helped Huxleys infer actin & myosin properties
Why would it be easier halfway up a chin-up than starting from a position of
fully extended arms?
optimal overlap of actin and myosin as opposed to too little overlap
Heart muscle does not follow the length-tension relationship of skeletal
muscle. Why is this important?
Fuller ventricle is capable of generating more force of contraction
What treatment would alleviate some of the muscle weakness from autoimmunity to
the nicotinic channel?
anti-acetylcholinesterase like neostigmine
Lowering extracellular Ca2+, Katz did his Nobel Prize winning work as he
converted the end plate potential to miniature end plate potentials elicited by
"quanta." What is the physical appearance of the quantum he witnessed
physiologically?
vesicle
The channel carrying the action potential in the T (transverse) tubule is
closely linked to what important component in muscle contraction?
sarcoplasmic reticulum (the Ca2+ channel)
What prevents the myosin head from binding actin in striated muscle when a
contraction is not called for?
tropomyosin
How would motor units differ in the extraocular muscles (responsible for eye
movements) vs. calf (gastrocnemius) muscle?
fewer muscle cells per neuron in muscles for finer movement
Which cell is damaged in ALS (amyotropic lateral sclerosis, Lou Gehrig's
disease)?
spinal motor neuron
In smooth muscle, what can phosphorylated myosin light chain do that the
unphosphorylated protein cannot?
bind actin
Gamma fibers preset the stretch receptor by causing what specific type of fiber
to contract?
intrafusal (or nuclear chain)
What is created from glycogen by glycogenolysis?
glucose (or glucose 6-phosphate)
What type of cell uses phosphocreatine (creatine phosphate)?
striated muscle
If there is lactic acid formation, oxygen debt, and creation of only a few ATPs
per glucose molecule, what is this type of metabolism called?
anaerobic glycolysis
Varicosities on autonomic nerves are used to control what kind of muscle?
smooth muscle
Without Ca2+ what does tropomyosin block?
Binding sites on actin for myosin
What transmitter and transmitter receptor are used at the motor end plate?
Acetylcholine nicotinic
Why would curare, by itself, be a poor choice for anesthetizing a patient for
surgery?
It is a paralytic, not an anesthetic
In what way does a graph of tension as a function of time look different for
complete vs. incomplete tetanus?
Bumpy for incomplete
In what way does smooth muscle's myosin light chain kinase (MLCK) substitute
for striated muscle's troponin-tropomyosin complex?
Phosphorylation of myosin allows cross-bridges
Here is a partial list of the proteins of striated muscle: actin, myosin,
troponin, tropomyosin. Name another.
titin, dystrophin, myoglobin
What happens specifically when either phosphate or ADP (you pick one) comes off
the myosin?
myosin binds to actin and power stroke is taken
One sarcomere goes from the z-line (z-disc) to (where)?
the next z line
How would the H zone look in the biceps at the bottom of a chin-up vs. at the
top?
H big at bottom, small at top
T-tubules (transverse tubules) are best known for their channels for which ion?
Ca2+
If you are not active at the time, after a meal, "in times of
plenty," glucose is imported into muscle and converted into what?
glycogen
What would happen to the end plate potential elicited by one spike in the motor
neuron if the extracellular concentration of Ca2+ in the vicinity of the
neuromuscular junction were reduced?
become smaller, become ), 1 or several miniature potentials
By what mechanism does neostigmine help a patient with myasthenia gravis?
increase acetylcholine to better stimulate what is left of the nicotinic
receptors
What is the limiting factor that requires the body's muscles to go to anaerobic
glycolysis for extreme exertion?
heart's ability to deliver O2
What is the X-axis (abscissa) for the oxyhemoglobin dissociation curve, the
graph that shows that myoglobin has a higher affinity for oxygen than
hemoglobin?
partial pressure of O2 in mm Hg
What is a nuclear chain fiber used for?
intrafusal muscle to preset stretch receptor
Why can't myosin bind to actin unless it's supposed to?
tropomyosin blocks the sites on actin for myosin binding
Which muscle protein changes configuration, power stroke and back stroke, for
muscle contraction?
myosin
Put in order from large to small three alternative, anatomical, words for
muscle cell, the subcomponents that make up the cell, and the muscle proteins
that make up these subcomponents.
cell=fiber, myofibril, filament=protein
How does the conversion of ATP to ADP affect creatine?
creatine becomes creatine phosphate
What is the function of gamma fibers and their connection to nuclear chain
fibers?
preset stretch for stretch receptor
Under the influence of Ca2+-calmodulin, what protein in smooth muscle gets
dephosphorylated?
myosin light chain kinase
Give one way the neuromuscular junction is distinguished from the typical
synapse in the nervous system.
larger, only excitatory
In terms of the muscle proteins, why is the muscle weaker when it is full
length or stretched?
less actin myosin overlap
In terms of muscle proteins, why does the length of the H (helle) zone vary
with muscle length?
myosin without overlap with actin
Where is the lactic acid that is built up in muscle taken care of?
liver
Ca2+ channels in the t- (transverse-) tubules are in contact with Ca2+ channels
in what subcellular structure.
sarcoplasmic reticulum
What famous drug paralyzes skeletal muscle by blocking the muscle membrane
receptor?
curare
What is the cause of the disease of muscle weakness in which nicotinic
receptors are lacking?
autoimunity to nicotinic
What enzyme is deficient in familial cases of Lou Gehrig's disease?
Super Oxide Dismutase
How does the oxyhemoglobin dissociation curve explain the offloading of oxygen
when blood arrives at muscle?
myoglobin's curve is to the left
Striated muscle's tension (strength) depends on its length. Out of A-band,
I-band, and H-zone, which ones change size (as a function of muscle length) and
which do not?
A stays the same, I and H would change
Why did they call one muscle protein "dystrophin?"
before they knew anything about function, they identified it as deficient in
muscular dystrophy
Calcium ions would indirectly regulate whether ATP is used in muscle. Why wouldn't
ATP replace ADP if calcium had not done what it does?
myosin needs to be able to bind actin for that ATP cycle to be able to run
What happens to tropomyosin to allow (or not) muscle contraction?
it exposes (or blocks) binding sites for myosin on the actin
Sir Bernard Katz won his Nobel Prize for demonstrating the quantal nature of
transmission at the neuromuscular junction. What happened when he lowered the
extracellular Ca2+?
fewer (for instance 0, 1, or 2) vesicles (his quanta) were released
From the depolarization at the nicotinic receptors of the motor end plate, an
action potential (using activated Na+ channels) moves down the sarcolemma
(muscle cell membrane). That triggers what other channels? (Your answer could
state what ion or what cellular component.)
calcium in both t-(transverse)-tubules and sarcoplasmic reticulum
In human surgery (and in animal research), you cannot tolerate muscle movement.
Why do you need to be particularly careful about using muscle relaxants?
you need to be certain the patient (or animal) is sufficently anesthetized
because paralysis would prevent any communication of distress
What is the significance of myoglobin's curve being to the left of hemoglobin's
curve (on the oxyhemoglobin dissociation graph)?
hemoglobin would offload oxygen to muscle
In contrast with the type of cell an alpha motor neuron innervates, what does
the gamma neuron connect to?
intrafusal muscle in the muscle spindle
Intracellular Ca2+ is exquisitely orchestrated. In contrast with the calcium
binding protein of striated muscle, what is the calcium binding protein of
smooth muscle?
calmodulin
Striated muscle has an optimum length, and it's strength (tension) drops off
when it is longer or shorter. In what way is the ventricular myocardial muscle
strikingly different?
The fuller (more stretched) the ventricle, the more forceful the contraction
Why is a corpse at a crime scene referred to as a "stiff?"
When ATP runs out, actin stays bound to myosin
Why would neostigmine ameliorate the condition of myasthenia gravis?
Shortage of nicotinic channels is somewhat overcome if there is more ACh
What cell is deficient in Lou Gehrig's disease (ALS=amyotropic lateral
sclerosis)?
Spinal motor neuron
What are varicosities with respect to control of smooth muscle?
NE is released not so much by synaptic terminals but by many swellings along
the axon
this page was last revised 6/25/09
**The autonomic nervous system lecture
Fox Chapter 9 (plus
selections from Chapters 7, 8, 14 & 20)
Autonomic n.s.
It's a motor system
Fig. 8.28
Fig. 9.3
motor system for smooth muscle and glands
contrasted with somatic system innervating striated (skeletal) muscle
Autonomic has preganglionic and postganglionic output
Fig. 7.3
Another figure to show the same thing
Parasympathetic and sympathetic
TRANSPARENCY (From an intro book)
Parasympathetic = "rest and digest"
Sympathetic = "fight or flight"
Fig. 9.5 [Fox's version of this same classic figure]
Parasympathetic, cranio-sacral, ACh (nicotinic and muscarinic), ganglion near
target
Sympathetic, thoraco-lumbar, ACh (nicotinic) then NE, ganglion near spinal cord
Acetylcholine and Norepinephrine
Fig. 9.7
(same material on next two lines)
Parasympathetic, cranio-sacral, ACh (nicotinic and muscarinic), ganglion near
target
Sympathetic, thoraco-lumbar, ACh (nicotinic) then NE, ganglion near spinal cord
Fig. 9.10
(same material on next two lines)
Parasympathetic, cranio-sacral, ACh (nicotinic and muscarinic), ganglion near
target
Sympathetic, thoraco-lumbar, ACh (nicotinic) then NE, ganglion near spinal cord
For NE (adrenergic), all receptors are G-protein-coupled-receptors
Alpha (vasoconstriction) phenylephrine (Neosynephrine, nasal decongestant) is
agonist
Beta-1 in heart, why beta blockers like propranalol were given for high blood
pressure
Beta-2 bronchioles, why asthma inhalers had epinephrine
Fig. 9.5 [again]
Many targets are "push-pull" like heart
Some are unique like arterioles (sympathetic only) -- close in peripheral
vascular beds (make hands cold), open in muscle (hyperemia).
Anatomy
Fig. 9.3
arrangement of sympathetic output from lateral horn neuron -> white ramus
-> sympathetic ganglion -> gray ramus
Simpler for parasympathetic, i.e. from brain stem nucleus or lateral horn in
sacral cord to parasympathetic ganglion
called enteric for gut. Contribution of neural network (plexus) to circular and
longitudinal muscles to mediate peristalsis. Parasympathetic allows digestion,
sympathetic puts it on hold. Atropine blocks muscarinic synapses and is in
anti-diarrhea medications to slow motility.
Beautiful women
Clinical Box on page 253
Atropine muscarinic antagonist
Atropa belladonna (beautiful woman) [deadly nightshade]
SLIDE (Hess, Scientific American, Nov. 1975, p.111) Women are more beautiful
with dilated pupils
Channels vs G protein-coupled receptors
Fig. 9.11
use nicotinic and muscarinic to remind you of ionotropic and metabotropic
Heart as an example.
Fig. 14.5
Automaticity at SA and AV nodes (spread from myocardial cell to next myocardial
cell). Sympathetic speeds heart, parasympathetic (via vagus, X) slows, and
relaxed heart rate is slower than automatic rate.
Male sexual function as an example.
Important aspect of quality of life
Fig. 20.22
(this is not quite true, see below)
Robert F. Furchgott, Louis J. Ignarro, Ferid Murad Nobel 1998
"for their discoveries concerning nitric oxide as a signalling molecule in
the cardiovascular system"
A few years ago, I wrote, "This is the only place where parasympathetic
affects arterioles, dilating them in corpus cavernosum for erection.
Sympathetic contributes to ejaculation."
Then I read a paper by Ignarro and then his Nobel "speech." Actually,
for erection (relaxing arteriole smooth muscle), adrenergic (via alpha 1
receptors) contracts smooth muscle, cholinergic (via muscarinic receptors)
inhibits adrenergic-induced-contraction (resulting in relaxation); more than
cholinergic and adrenergic, a little mentioned autonomic component, the NANC
(nonadrenergic noncholinergic) system, mediates relaxation.
In the 2003 movie Something's
gotta give, Jack Nicholson has a heart attack while having sex, and the
docs ask if he is on Viagra as they are about to give him nitroglycerine. (also
listed in advertisements for ED (erectile dysfunction) medications because of
interaction and resulting low blood pressure)
People take nitroglycerine for angina (chest pain), and it releases NO (nitric
oxide) and relaxes the coronary arteries
Nitric Oxide (NO), made by endothelial nitric oxide synthase (eNOS), unusual in
that it diffuses across "postsynaptic" membrane to affect guanylyl
cyclase (GC) involved in making cGMP.
NO was endothelial derived relaxation factor (EDRF), mediator of
parasympathetic nervous system's dilation of arterioles in corpus cavernosum.
Viagra (sildenafil) inhibits the PDE that breaks down cGMP
Exam questions from 2004 - 2008 relevant to this outline
What chemical does Viagra inhibit?
the phosphodiesterase for cGMP
What gas mediates arteriole dilation by the parasympathetic nervous system?
NO (nitric oxide)
A nasal decongestant spray would contain an agonist for what naturally ocurring
neurotransmitter?
norepinephrine
The anatomical term "cranio-sacral" refers to what functional unit?
parasympathetic nervous system
For what condition was propranalol, a "beta blocker," given?
high blood pressure
The anatomical term "thoraco-lumbar" refers to what functional unit?
sympathetic
An asthma spray would contain an agonist for what naturally ocurring
neurotransmitter?
norepinephrine
Where are nicotinic receptors used in the autonomic nervous system?
ganglia
In addition to cranial nerves, what other nerves make up the parasympathetic
nervous system?
sacral
What is the corpus cavernosum?
erectile tissue
Muscarinic receptors are for what neurotransmitter molecule?
acetylcholine
What would sympathetic activation do to the blood flow in muscle?
increase it
Identify one of the two parts of the central nervous system where the
parasympathetic output originates. Be specific.
Brain (for cranial nerves) and sacral part of the spinal cord
Propranalol is a btea-1 blocker, and it is given to patients to prevent the
action of what neurotransmitter at what site?
norepinephrine in heart
A patient comes in and his heart is stopping because of exposure to malathion.
What do you give him?
atropine
Why would atropine be a useful ingredient in medication for diarrhea with
cramping?
inhibits parasympathetic meciated activation of gastrointestinal motility
Why are treatments like nitroglycerine contraindicated for men who are on drugs
for erectile dysfunction?
An unsafe drop in blood pressure would result from too much smooth muscle
relaxation
"The parasympathetic nervous system dilates arterioles in the corpus
cavernosum, mediating erection." Give either of the reasons that this
statement is not the whole truth according to more modern research.
(1) actually, the parasympathetic nervous system inhibits the sympathetic for
this. Also (2) a non-cholinergic non-adrenergic system is of paramount
importance.
"Nicotinic" applies to which place (i.e. preganglionic axon terminal,
postganglionic synaptic receptors, postganglionic axon terminal, effector
receptors)? Justify.
The acetylcholine receptor on the postganglionic cell body
What specific kind of receptor does atropine block?
Cholinergic muscarinic
Where does nicotine have its effect?
on nicotinic acetylcholine receptors most notably in autonomic ganglia
What is the significance of the endothelial cells that line blood vessels in
mediating erection?
endothelial derived relaxation factor (EDRF= nitric oxide[NO]) is made there
In which part of the autonomic nervous system is the ganglion near the
neuroeffector junction?
parasympathetic
What specific type of receptor mediates the sympathetic nervous system's
effects on the heart?
beta-1
Hyperemia, increased blood flow in skeletal muscle, is mediated by what
functional subdivision of the nervous system?
sympathetic
How does a nasal decongestant spray like phenylephrine work?
constricts arterioles
Why would a beta blocker like propranalol be given for high blood pressure?
would block beta adrenergic receptors in heart, decrease heart rate and force
or volume
How does Viagra work?
inhibit PDE to break down cGMP
What kind of muscle does the autonomic nervous system connect to?
smooth
Usually your eye care professional will administer something to dilate the
pupils. What type of receptor for what neurotransmitter is blocked?
muscarinic for acetylcholine
For which component of the autonomic nervous system is the ganglion closer to
the central nervous system?
sympathetic
Explain how vasoconstriction (or the opposite) applies to how a decongestant
unclogs a stuffed nose.
An alpha agonist like phenylephrine constricts engorged vascular bed
"Control of arteriole smooth muscle involves "unique"
innervation, sympathetic only. Except for (what?).
arterioles to the corpus cavernosum
"This and other erectile dysfunction medications should not be taken if
you are taking nitrates for chest pain." Why not?
the combined actions, all causing relaxation of arteriole smooth muscle, would
cause an unsafe drop in blood pressure
this page was last revised 6/25/09
**The energy lecture
Energy metabolism
Readings
Fox selections from Chapters 2, 4, 5, 6, and 11
"He said science was going to discover the basic secret of life
someday," the bartender put in. He scratched his head and frowned.
"Didn't I read in the paper the other day where they'd found out what it
was?"
"I missed that," I murmured.
"I saw that," said Sandra. "About two days ago."
"That's right," said the bartender.
"What is the secret of life?" I asked.
"I forget," said Sandra.
"Protein," the bartender declared. "They found out something
about protein."
"Yeah," said Sandra, "that's it."
-Kurt Vonnegut, Jr. Cat's Cradle
Overview
We will not get very technical on biochemistry of metabolism, since this is a
physiology course and not a biochemistry course.
Reminder
Metabolism is the general term for two kinds of reactions:
(1) catabolic reactions (breakdown)
and
(2) anabolic reactions (constructive)
Organic Chemistry is the chemistry of carbon (C) which makes 4 bonds.
In "Star Trek" (the first movie), people were called "carbon
based units" by the alien.
Carbohydrate
Fig. 2.13a
Carbohydrate (Carbo-hydrate is also sort of a compound word, carbon,
"hydrate" suggests water) - the general formula is Cn(H2O)n
Monosaccharides
Hexose (hex = 6 [carbons], "-ose" always means sugar)- glucose, the
most famous monosaccaccharide, is good to illustrate that monosaccharides
usually assume a ring structure
Fig. 2.15
Compound dehydration synthesis puts sugars together
Hydrolysis (hydro-water, lysis-breakdown) is the opposite.
In digestion, macromolecules are broken down to monomers.
Disaccharide - sucrose, lactose (milk)
Figure shows maltose and sucrose, and shows dehydration synthesis.
Fig. 2.14
Polysaccharides starch (plant), glycogen (glyco-sugar, gen-give birth to)
(animal)
Energy storage:
In liver for whole body
In muscle for muscle use
Fat
Fig. 2.19
Lipids (fats) store more energy (2x sugar) 1 tablespoon of sugar is 50, fat 100
"Calories" = kilocaloriies
Glycerol & 3 fatty acids (16-24 C long) - triglyceride ester bonds , note
the dehydration synthesis
The -COOH defines an organic acid such as a fatty acid, otherwise the molecule
is a hydrocarbon.
C-C (single bond) vs. C=C (double bond) unsaturated (vs saturated with H's),
with several, it is referred to as "polyunsaturated" PUFA =
polyunsaturated fatty acid
Animal fats tend to be saturated, bad for arteries leads to atherosclerosis; vs
vegetable fats better.
Polar phospholipids - we'll talk about that later, because our emphasis now is
energy.
Steroids-cholesterol & hormones - we'll talk about that later, because our
emphasis now is energy.
Salts of cholesterol are in bile (from liver) that acts like a detergent to
emulsify fats to aid in digestion.
Protein
Fig. 2.27
short = "Peptides", medium = polypeptide, long = "protein"
(hundreds, thousands of amino acids)
The general formula is NH2-CR-COOH - amino ( -NH2 ) and acid ( -COOH ).
Peptide bonds involves -NH2 and -COOH getting linked with a dehydration
synthesis.
There are about 20 amino acids (alphabet of 20 letters)
R group varies, see figure.
About half of the amino acids are "essential" meaning that they
cannot be made by metabolic conversion from other molecules and thus need to be
eaten
Structure:
1. primary (the sequence)
2. secondary (alpha helix, beta pleated sheet)
3. tertiary structure (disulfide and other bonds)
4. quaternary structure (chains interact with each other)
Here is a really important example - hemoglobin - which has 2 alpha subunits
and 2 beta subunits and a heme group.
Figure 5.16
Important to the topic of energy in physiology, amino acids can be used for
energy, nitrogenous waste must be eliminated as urea.
Biological energy
Fig. 4.15
ADP plus phosphate <-> ATP involved in storage and release of energy
[typo on transparency, but o.k. in book]
ATP made of Adenine, ribose and 3 phosphates, energy stored in 3rd phosphate
bond
It is interesting to note that ATP delivers it's energy by transferring its
phosphate to molecules (you will see this several times in diagrams throughout
the semester)
Energy - kinetic and potential (discussing bioelectricity, potential will also
be Volts)
BTU's (British thermal units, which can be converted to calories) imply that
energy and heat are related.
Heat stored in energies of covalent bonds in kcal / mol
Free energy can be used for work = what is stored in bonds minus what is wasted
as heat
cellular respiration C6H12O6 -> 6CO2 +6H2O + energy
the free energy is 686 kcal/mol
ATP to ADP
38 of them generated when respiration is complete
40.3% efficient, the rest is heat, usually considered as waste but useful in
temperature regulation in warm blooded animals, homoiotherms, homeotherms.
Reminder - "count" "calories"= kcal
2000 per day for a sedentary adult woman
Important that we do not lose calories (through urine or feces) except through
urine in untreated diabetes.
Marathon - 3000 Cal aerobic. 100 yd dash -anaerobic
We get our energy mostly from (1) glucose, (2) glycogen (glyco-sugar, gen-give
rise to) in muscle for use in muscle and in liver for glucose release to blood,
(3) amino acids (with NH3 as waste), or (4) fat (mostly fatty acids are chopped
down 2 carbons at a time to give acetic acid into acetyl CoA in the Kreb's
cycle).
Photosynthesis to make glucose, cellular respiration to release energy
Reaction [for glucose, C6(H2O)6]: C6H12O6 + 6 O2 -> 6 CO2 + 6 H2O
Overall, 1 glucose can give up to 38 ATP's, a few from glycolysis and the rest
from the mitochondrion
Glycolysis and anaerobic glycolysis
Background
It is important to introduce NAD+ plus 2 H <-> NADH in oxidation -
reduction reactions as a way to carry electrons.
lose electrons - oxidation (NAD+ is oxidized)
nicotinamide adenine dinucleotide
add electrons - reduction (NADH is reduced)
Fig. 5.3
Glycolysis is a compound word glyco-sugar, lysis-splitting. Glucose is split
into 2 pyruvic acids
Use 2 ATP's make 4, net 2 make 2 NADH's plus 2 H+'s, the H+'s come from from
"sugar"
Fig. 5.4
This was covered in muscle lecture
without oxygen, make lactic acid.
Anaerobic glycolysis is used to deliver ATP quickly but wastefully (squandering
glucose).
Make ATP's but need to regenerate NAD+ from NADH to make.
Lactic acid contributes to fatigue in muscle and oxygen debt, and the liver
eventually reconverts.
Anaerobic cellular "respiration" is needed in times of extreme
exertion because the heart (cardiac output) is the limiting factor in delivery
of oxygen to muscle.
Fig. 5.5
Polysaccharides
Glycogen - animal starch, polymer of glucose
High in muscle where it provides glucose for local use
High in liver where it provides glucose when fasting
Cellulose - cannot digest - "fiber"
Regulation by the hormone epinephrine (adrenalin)
Fig. 11.10
Epinephrine involved in stimulating liver to release glucose
Earl W. Sutherland, Jr. (from the US) won the 1971 Nobel Prize
for mechanisms of hormone action.
It pertained to that beta adrenergic part and cAMP, a "second
messenger" or part of a signal transduction "cascade."
So Sutherland is sometimes considered the founder of "signal
transduction."
Note that there is a separate alpha adrenergic effect too
Glycolysis and the Kreb's cycle
Fig. 5.12
Pyruvic acids generate 2 acetic acids, become Acetyl CoA's.
Kreb's cycle = citric acid cycle = TCA (tricarboxylic acid cycle)
Takes place in the mitochondrion
A few ATP's are made plus NADH's and FADH2 are generated
CO2 is generated here.
The1953 Nobel
prize in Physiology and Medicine was divided equally, one half awarded to:
SIR HANS ADOLF KREBS for his discovery of the citric acid cycle and the other
half to: FRITZ ALBERT LIPMANN for his discovery of co-enzyme A and its
importance for intermediary metabolism.
sugar-H2 + NAD+ -> (DEHYDROGENASE) "sugar" + NADH + H+
(in other words, H is split to H+ and e-)
Electron transport and oxidative phosphorylation use oxygen
cytochromes - these are iron - containing pigments (iron is in the form of
heme)
NADH and FADH2 give electrons to cytochromes and oxygen
Protons pumped, then flow down gradient making ATP's.
Something like an ion pump (we will covered that later in the semester) in
reverse is how most ATP is made, H+ (pH, proton) gradient runs through that
molecule, like water running through turbines generating electricity, to
generate ATP
How does glucose get into the cell?
Fig. 6.16
Facilitated diffusion for glucose transport
Fig. 6.17
Insulin causes glucose transporters to be inserted to the membrane
Fig. 6.20
There is another kind of glucose transporter where Na+ (already pumped with
ATP) drives it
Fig. 11.11
The receptor for insulin is a membrane spanning tyrosine kinase that dimerizes
Kinase means that the enzyme phosphorylates a protein
Tyrosine refers to the fact that phosphorylation is on tyrosine (an amino acid)
residues.
Obviously, this would take place on the intracellular side of the membrane
Questions from 2004 - 2008 tests that pertain to this lecture
What does a kinase do to a protein?
phosphorylates it
How does glucose get into a cell?
you need a membrane protein for diffusion
What is the activity of the insulin receptor enzyme?
tyrosine kinase
What is the polymer of glucose that is so important in muscle and liver
metabolism?
glycogen
How is it that facilitated diffusion of glucose is increased by insulin?
more GLUT4 transporters deployed to membrane
The opposite of dehydration synthesis (condensation reaction) happens in
digestion. What is this called?
hydrolysis
About how many ATPs do you get from full aerobic metabolism of one glucose
molecule?
38
During anaerobic metabolism in muscle, what is pyruvic acid converted to?
lactic acid
What is the function of salts of cholesterol made by the liver and secreted
into the small intestine?
emulsify fats
When I remind you that the insulin receptor is a tyrosine kinase, where is
tyrosine and what happens to it?
on intracellular side of enzyme, tyrosine (amino acid) becomes phosphorylated
What second messenger activates protein kinase when the beta-adrenergic
receptor of a liver cell binds epinephrine?
cAMP
In your body, what becomes of the amine of an amino acid if you use that amino
acid for calories?
becomes ammonia that gets converted to urea
In your digestion, macromolecules are hydrolyzed. What is the name of the
opposite reaction that had been used to string together monomers into a
polymer?
dehydration synthesis
Arachidonic acid has 4 double bonds. What is the term for such a molecule?
polyunsaturated fatty acid
While fasting, what does the liver do with the glycogen it stores?
breaks it to glucose and sends that to the blood stream
How many pyruvic acids do you get from one glucose?
2
If a fatty acid were 14 carbons long, how many acetyl co-A's would be delivered
to the Krebs cycle if it were chopped down completely in catabolism?
7
Epinephrine, acting on the beta adrenergic receptor, causes what to happen to
glycogen in the liver?
breakdown to glucose and release to bloodstream
In addition to facilitated diffusion, there is a transport mechanism for
glucose requiring energy delivery from ATP. To what molecule does ATP deliver
its energy?
the sodium pump
In the biosynthesis of fat, to attach a fatty acid to glycerol via an ester
bond, what molecule must be removed?
H2O
Fatty acids are "chopped down" two carbons at a time to feed into
metabolism. Where do these two carbon components feed in (biochemically)?
acetate (acetyl CoA)
The need to regenerate NAD+ from NADH causes the formation of what from pyruvic
acid?
lactic acid
What molecules are generated from the complete aerobic cellular respiration of
glucose (in addition to energy)?
H2O and CO2
What are the salts of cholesterol of bile used for?
emulsify fats in digestion
Chemically, how is a polyunsaturated fatty acid different from a fully
saturated fatty acid?
Double C=C bonds
What do we have to get rid of if we use amino acids for energy?
Nitrogenous waste
The hormone epinephrine (adrenalin) is sometimes considered the "first
messenger" to signal the liver of the need to release glucose. Within the
liver cell, what has been called the "second messenger" in this
signal transduction cascade?
cAMP
What is urea made from and where does the body make it?
NH3 and CO2 in the liver
Describe the structure of hemoglobin in terms of protein subunits and the units
where iron is located.
2 alpha and 2 beta protein chains each with a heme group
How is it that a liver secretion can emulsify fats to aid in digestion?
salts of cholesterol would have hydrophilic and hydrophobic sides
On the way to the Kreb's cycle, fatty acids are chopped down two carbons at a
time to make what?
acetic acid or acetyl coA
"H is split to a proton and an electron." To achieve what?
to drive proton pump then capture energy of proton pump to make ATP
How can a cell's ability to take up glucose be so different with vs without
insulin?
insulin causes the membrane deployment of transporters
What molecule donated the phosphate when insulin prompted the insulin receptor
dimer to phosphorylate itself?
ATP
What would a beta adrenergic receptor on a liver cell mediate?
glycogenolysis
For one type of glucose transporter, not the facilitated diffusion, energy is
required. How is that energy delivered?
when glucose is cotransported with Na+, the sodium pump
Carbon dioxide plus (what?) are converted into urea in the liver.
ammonia (NH3)
Polymers (macromolecules) are constructed from their building blocks by (what
process)? (the opposite of how they are broken down in digestion)
dehydration synthesis (as opposed to hydrolysis)
"Salts of cholesterol" - relate to digestion. (Your answer could
refer to an organ or a process.)
from the liver into the duodenum (small intestine) to emulsify fat
Sutherland's Nobel Prize winning work had cAMP as the "second
messenger." For the "first messenger," what is the type of
receptor on the surface of the cell?
beta adrenergic
How does fat feed into metabolism to render ATP? (An answer for either type of
components that make up a fat will be OK.)
glycerol gets converted to the precursor of pyruvic acid. Fatty acids get
chopped down 2 carbons at a time to become acetyl CoA
"You're not going to get carbon dioxide from anaerobic glycolysis"
because it is made in what specific step?
Krebs cycle
Why would you ultimately need energy (ATP) for one type (which type?) of
glucose transporter?
the one that uses sodium ions running down their concentration gradient - those
ions need to get pumped back out
What use is made of protons (H+, hydrogen ions) running back down their
concentration gradient (after they had been pumped up that gradient)?
This is the "water turbine" to generate ATP
"Tyrosine kinase" - where did the phosphate come from?
ATP donates the phosphate there (and pretty much everywhere)
Amino acids can be used for catabolic energy. Where do they feed into the
metabolic mill?
Into pyruvic acid just before acetyl co-A
What would a beta adrenergic receptor on a liver cell mediate?
Via cAMP, increase conversion of glycogen to glucose
this page was last revised 6/25/09
**The metabolism lecture
Control of
metabolism, Fox, Chapter 19 (also some
other chapter figures, 11 and 3)
General considerations
Control of energy metabolism is so important that there are two major hormones
(insulin and glucagon, proteins from the pancreas), as well as many others
(thyroxine, epinephrine, and cortisol) to regulate it on short- and long-term
bases.
In a lab...
...(BL A347, Fall, 2004), we injected insulin into mice, decreasing glucose,
then injected glucagon, bringing it back up. Data: before: 157 mg/dl. after
insulin 49, after glucagon 197.
More on insulin and glucagon
Fig. 11.29
In pancreas, which is largely a digestive exocrine gland, there are also islets
of Langerhans (as shown in this picture from our histology course) which
are the endocrine glands where the beta cells make insulin and the alpha cells
make glucagon
Fig. (like 11.31a)
Pancreas Insulin- sugar uptake into cells (blood sugar down), make glycogen in
liver
Fig. 3.23
2 peptides clipped from one chain held by disulfide bonds
(this sort of processing is common for signalling molecules)
Diabetes mellitus
Type 1 autoimmune disease beta cells are destroyed, young people, insulin
dependent
inject insulin. protein, must inject
(vs steroid like "the pill" which can be taken orally)
Type 2, older people, genetic, correlated with overweight, non-insulin
dependent
sugar in urine- can't pump back, in our physiology labs, we use
these urinalysis
strips which include a test for glucose in the urine. In the aforementioned
endocrine lab, we introduced the students to this type of strip
and meter for testing blood glucose.
Eye problems (too many new blood vessels - angiogenesis) and cardiovascular
problems
Brain is not insulin-dependent - coma from too much insulin because no glucose
for brain
Glucagon mobilize sugar to blood like adrenalin
sugar regulates insulin and glucagon
Glucose (and other calories)
Review
Fig. 19.2
Fat, carbohydrate and protein feed into metabolism
What you may not have seen before this figure is ketone bodies, produced from
fatty acids in liver.
Low carbohydrate diet and diabetes can lead to ketosis, even ketoacidosis.
Note also that this figure shows that urea is the nitrogenous waste from using
amino acids for calories.
Fig. 11.31
Blood glucose up, insulin up, glucagon down, cells use glucose
Blood glucose down, insulin down, glucagon up, glycogenolysis &
gluconeogenesis (making of glucose from molecules like amino acids.
Fig. 19.10
The above is given in more detail relative to after meal vs fasting
What the liver does
Fig. 19.9
Here's what the liver does to release:
glucose (from glycogen and amino acids)
and
ketone bodies (from fat and amino acids)
When you fast, fat and muscle are broken down
Fig. 19.7
Opposite when insulin (and glucose) are plentiful:
Fat deployed (and not released) from adipose tissue
and
Glycogen deployed (and glucose not released) from liver
How glucose is monitored
Fig. 19.8
How glucose is monitored by a beta cell
glucose is transported in by GLUT2
metabolism makes ATP
ATP is ligand that closes K+ channel
cell depolarizes
voltage gated Ca2+ channel lets in Ca2+
exocytosis from vesicles with insulin
Signal transduction
Fig. 11.11
Insulin receptor is tyrosine kinase
a dimer
crosses membrane
binds insulin extracellularly
puts phosphates on tyrosine residues
Fig. 19.14
Like for epinephrine, receptor for glucagon is G protein coupled receptor
For the umpteenth time, I show you signal transduction cascade
One fact on this figure not shown before:
cAMP acts by binding inhibitory subunits and pulling them off catalytic
subunits of PKA
The kinase phosphorylates enzymes, activating some and inhibiting some
end result, of course, is glycogenolysis in liver and lipolysis in adipose
tissue
Glucocorticoids
Fig. 19.15
Glucocorticoids are also involved in stress (mobilizing molecules for
catabolism)
Glucose, fatty acids, ketone bodies and amino acids in blood increase.
This is slower than for epinephrine
Test questions from 2004 - 2008 that relate to this outline
What is the ligand that closes the K+ channel in the beta cell's mechanism for
monitoring glucose?
ATP
What is the activity of the insulin receptor enzyme?
tyrosine kinase
What is the polymer of glucose that is so important in muscle and liver
metabolism?
glycogen
In the process where epinephrine causes glucose release from liver, what enzyme
does cAMP activate?
protein kinase A
In fasting, gluconeogenesis can provide some glucose from amino acids. Where do
these amino acids come from?
muscle
If you had a lot of ketone bodies, what does that tell you about what is going
on in your metabolism?
you are using fats, probably fasting
How is glucose detected by b cells in the islets of Langerhans?
being metabolized to make ATP, ligand for channel
Insulin injected into an anesthetized mouse would decrease blood glucose. What
other hormone, normally produced in the islets of Langerhans, would raise the
glucose levels back?
glucagon
When I remind you that the insulin receptor is a tyrosine kinase, where is
tyrosine and what happens to it?
on intracellular side of enzyme, tyrosine (amino acid) becomes phosphorylated
Epinephrine, acting on the beta adrenergic receptor, causes what to happen to
glycogen in the liver?
breakdown to glucose and release to bloodstream
In addition to facilitated diffusion, there is a transport mechanism for
glucose requiring energy delivery from ATP. To what molecule does ATP deliver
its energy?
the sodium pump
The insulin receptor dimerizes when it binds insulin. What do these molecules
do that gives them the description "tyrosine kinase?"
they phosphorylate the amino acid tyrosine
If you need to take insulin, why do you need to inject it?
if you ate it the protein would be broken down
As it applies to diabetic retinopathy, what is angiogenesis?
formation of new, fragile, blood vessels
What holds the two peptide chains of insulin together?
disulfide bonds
What process is mediated by the entry of Ca2+ into the pancreatic beta cell?
release of vesicles
What allows the return of the inhibitory subunit to the catalytic subunit of
protein kinase in the signal transduction pathway for glucagon?
conversion of cAMP to 5'AMP
Under what circumstances would ketone bodies be released from the liver?
fasting
What would insulin cause an adipose cell to do?
take up glucose
What donates the phosphate when the insulin receptor gets phosphorylated?
ATP
"Insulin is a receptor tyrosine kinase." Receptor - it is a receptor
molecule." Kinase - it is an enzyme that phosphorylates proteins. What
does the word tyrosine imply?
it is the amino acid that gets phosphorylated
Why can't you just swallow insulin (instead of injecting it)?
would be broken down in digestion
How is cAMP made? (Answer either [1] what is the precursor? or [2] what is the
enzyme?)
ATP -> adenylyl cyclase
Facilitated diffusion for glucose transport does not utilize ATP. Under what
circumstances does ATP get used for glucose transport?
Indirectly, Na+K+ATPase, to let Na+ drive co transport in kidney tubule and gut
What would an injection of glucagon do to the blood glucose level?
raise it
I repeated the point "Insulin increases glucose transport into cells in
insulin-dependent tissues like liver, muscle and adipose tissue." What is
the most important non-insulin-dependent part of the body?
brain
What is gluconeogenesis?
forming glucose from other molecules such as amino acids
What special job is there for the ATP that is generated by glucose metabolism
in the beta cell of the islets of Langerhans?
ATP is ligand that closes K+ channel to depolarize cell
What is released from adipose tissue under the influence of glucagons?
fatty acids
Give one phrase to describe Type 2 diabetes.
non-insulin dependent, correlated with overweight, affecting receptor, occuring
at a later age
What happens to the translated amino acid sequence to make the final insulin
hormone?
part gets cleaved off, 2 chains linked by disulfide bridges
Why would the physician deliberately burn holes in the retina (laser
photocoagulation)?
to decrease angiogenesis in diabetes
If the insulin/glucagon ratio favored gluconeogenesis, what would be happening
to the insulin dependent cellular uptake of glucose?
decrease
Under what circumstances would muscle be broken down for energy?
fasting
With respect to your eating habits, when would ketogenesis occur?
fasting
What happens to the membrane voltage when glucose signals a beta cell in the
islet, and how is ion flow affected to cause this electrical change?
depolarize, K+ flow decreased
How does cAMP activate PKA?
pull inhibitory subunits off catalytic subunits
What is the circuitous route by which cortisol causes the increase in blood
glucose?
muscles release amino acids that are converted to glucose in the liver
What is proinsulin, and how is this processed to make the active hormone?
It is a longer polypeptide, a chunk is chopped out of the middle, and the two
parts of insulin are tied together by disulfide bonds
How does destroying part of a diabetic's retina preserve vision?
It decreases the signal for angiogenesis
During fasting, what will happen to the level of ketone bodies in the blood?
increase
What hormone promotes the storage of triglyceride into an adipose cell?
insulin
How, specifically, is Ca2+ involved in how beta cells put out insulin?
When the beta cell depolarizes (ATP closes K+ channel) Ca2+ comes in, involved
in insulin vesicle release
he "water turbine" to generate ATP
"Tyrosine kinase" - where did the phosphate come from?
ATP donates the phosphate there (and pretty much everywhere)
Amino acids can be used for catabolic energy. Where do they feed into the
metabolic mill?
Into pyruvic acid just before acetyl co-A
What would a beta adrenergic receptor on a liver cell mediate?
Via cAMP, increase conversion of glycogen to glucose
What pancreatic hormone is increased during fasting?
glucagon
"ATP is the ligand that closes the K+ channel in the islet's beta
cell." What does this do to the electrical potential?
depolarize
What effect does cortisol have on adipose tissue?
Cause release of free fatty acids
this page was last revised 7/1/09
Circulation
Fox Chapters 13 and 14 (a figure from chapter 12)
Overview
In multicellular metazoan, need a vascular system (in terestrial plants above
mosses, xylem and phloem)
Circulation : Cardiovascular system
Anatomy of the heart
TRANSPARENCY (Review, Introductory Biology)
Fig. 13.10
Chambers of heart
Birds and mammals have 4 chambers
Note that right is drawn on left as if looking into the chest of a supine
subject (as I first mentioned when I lectured on Loewi's discovery of vagus
stuff, acetylcholine)
Here is the circuit: LA - LV - Arteries (aorta, etc.) (blood pressure taken
here) - Arterioles (regulate blood flow to muscles, brain, digestion, kidneys
and skin) - Capillaries (near, exchange, WBC's) - venules - veins (no pressure,
valves)- RA - RV - Pulmonary arteries - Lung capillaries - Pulmonary veins -
Heart valves and sounds
Fig. 13.11b
pulmonary valve (semilunar) feeds pulmonary arteries
aortic valve (also semilunar) feeds aorta
These valves snap shut from arterial back pressure at the end of systole to
make second heart sound- "dub"
Superior and inferior vena cava feed right atrium -> ventricle via tricuspid
(atrio-ventricular) valve.
Pulmonary veins feed left atrium -> ventricle via bicuspid
(atrioventricular) valve.
Tricuspid & bicuspid snap shut at start of ventricular contraction to make
first heart sound- "lub."
If there is backslosh through valves, this is called a heart murmur.
Blood vessels
Fig. 13.26
artery is like hose
blood flow to emptying into vascular bed: regulation by smooth muscle of
arteriole
capillary is one layer of endothelial cells (fenestrated or continuous)
TRANSPARENCY (Review, Introductory biology)
Fig. 14.25
- blood spreads out as it goes from arteries -> arterioles -> capillaries
and hence moves slower. Pressure goes down during movement arteries ->
arterioles -> capillaries (bottom).
Fig. 13.30
Blood moves slowly and with very little pressure in veins. Movement in veins is
mostly passive with a series of valves and where contraction of skeletal
muscles helps
Fig. 13.37
Lymphatic circulation helps to percolate interstitial fluid back to circulation
Fig. 14.23
Shunts (arteriovenous anastomoses) help to regulate circulation through
peripheral vascular beds.
Cardiac cycle and blood pressure
Fig. 13.13
cardiac cycle
Diastole (between heart beats), systole is during ventricular contraction,
hence terms systolic and diastolic blood pressure.
Fig. 13.14
Ventricle fills during diastole.
Ventricle empties during systole.
Ventricular pressure builds during systole.
Wiggers
diagram.
Relates ventricular pressure to arterial pressure.
Pulmonary pressure is lower than systemic.
Buildup of ventricular pressure opens valve and blood moves to aorta.
As ventricle relaxes, back pressure from artery snaps valve shut.
Ventricular filling
Fig. 14.2
Frank-Starling law.
The greater the ventricular filling, the greater the cardiac output.
This is good! -- recall that the tension length relationship for striated
muscle had a peak, but, if the muscle got too long, less force could be
generated.
This figure also shows that the sympathetic nervous system moves this curve up.
Measuring blood pressure
It is arterial blood pressure that is usually measured.
Fig. 14.30,
Fig. 14.31
close off artery, when it opens (systolic pressure), blood flow is turbulent
and noisy (Korotkoff sounds), when it is always open (diastolic pressure),
blood flow is no longer noisy
Blood pressure is measured in arteries
High blood pressure is called the "silent killer."
hypertension 45 million Americans - salt intake is still debated, >140/95
high 140/70 normal
high diastolic is especially bad
Explained by Wiggers diagram, if diastolic b.p. is high, then it takes higher
ventricular pressure before valve opens and blood actually moves.
Regulation of blood pressure
Fig. 14.27
Blood pressure is regulated by sensory receptors in aortic arch and carotid
sinus.
Goes to medulla oblongata of brain theh out to sympathetic and parasympathetic
nervous systems.
There are also brain influences that come down via hypothalamus.
Myocardial cells
Fig. 12.32
Heart muscle cells branch and come together and are joiined at intercalated
discs with gap junctions that spread the electrical signal from cell to cell.
cardiac muscle - automatic (explained below)
here is a picture
from our histology course
of heart muscle cells joined at intercalated discs
(like Figure 12.34)
Electrical activity of heart cells
Fig. 13.20
Electrical - SA (sinoatrial) node (or electrical pacemaker) - spread -
automatic.
Sympathetic nervous system speeds it up, parasympathetic nervous system slows
it down.
AV (atrioventricular node) is eventually stimulated.
If it were not, it is also automatic but slower and would generate a heart beat
in the venticals.
Bundle of His, bundle branches, and Purkinje fibers get ventricular
depolarization to happen almost synchronously.
Fig. 13.18
Pacemaker cells have depolarization during diastole because of slow Ca2+
channels.
Pacemake potential-HCN=hyperpolarization cyclic nucleotide (beta-1 adrenergic
affects cAMP)
Spike is from Fast Ca2+ channels and Na+ channels
Repolarization uses K+ channels.
Fig. 13.19
Ventricular myocardial cells have long action potentials involving the specific
channels shown.
The ECG
Fig. 13.24
Einthoven's triangle to show possible placement of EKG (ECG =
electrocardiogram) leads.
Because a lot of cells in heart work together, and because extracellular fluid
has high conductivity, electrical activity can be recorded non-invasively.
Fig. 13.22b
P is atrial depolarization.
QRS is ventricular depolarization.
T is ventricular repolarization.
Fig. 13.25
This figure relates EKG to pressure and sounds
Atherosclerosis
Fig. 13.26
(again)
Normally artery has
tunica externa
tunica media
tunica interna (endothelium and elastic layer )
Fig. 13.32
A layer of fat with ccholesterol between media and externa
ulceration lining lumen
atherosclerosis - hardening of the arteries - plaques
atheroma with macrophages
Cholesterol is a problem
Heart attack
General:
Myocardial cells not regenerate (by mitosis in the adult). This is why heart
attack is so damaging. The same is true for the nerves in the central nervous
system where similar damage is called stroke.
Coronary arteries clog -> myocardial infarction - coronary thrombosis -
ischemia (too little blood flow for oxygen delivery)
Angina, chest pain, and referred pain
Platelet aggregation - thrombus (local), embolism (from elsewhere) cause
ischemia
tissue plasmogen activator (TPA) dissolve clots
streptokinase thru catheter dissolve clot
aspirin inhibits clotting, coumaden is a strong anticoagulant
catheter with balloon angioplasty insert stent
fibrillation - CPR (keep brain alive, needs O2)
In CPR (cardiopulmonary resuscitation) chest pressure keeps blood flowing a
little and rescue breathing keeps blood oxygenated
1 million Americans die/yr reducing since 1971
bypass operations, replace coronary artery with vessel from somewhere else in
the body, there are 100,000-200,000/yr operations - 30% may be unnecessary
"heart attack" - myocardial infarction
heart muscle is aerobic
anaerobic metabolism would build up lactic acid and cause pain (angina
pectoris)
nitroglycerine relaxes smooth muscle (Viagra and other ED medications would be
contraindicated)
heart muscle damage by necrosis (as opposed to apoptosis - programmed cell
death)
can be detected in S-T of ECG
uncoordinated contraction of heart muscle - fibrillation
in atria fibrillation is not so important becaus atrial beat only addis a
little bit to ventricular filling
in ventricles, it is fatal and hence the importance of defibrillators
re-entry of excitation as electrical signal takes long route around scar tissue
after heart attack can contribute to poor ventricular coordination
Risk facrors for heart attack
(1) High blood pressure (the silent killer) -- Wiggers diagram --heart has to
work harder to open semilunar valves.
(2) prior heart attack
(3) smoking
(4) diabetes
(5) family history - a dominant allele in hypercholesterolemia (and other
genetic factors?)
(6) LDL-low density lipoprotein - made in liver - low LDL receptors help liver
take up cholesterol
LDL receptors take out cholesterol which otherwise deposits
HDL may lower deposition - excercise good for this
(7) clotting, especially clumping of platelets) inhibited by aspirin (and
coumadin) - hence term "coronary thrombosis" (in coronary artery)
Prevention -
(1) exercise - increase HDL (endothelial cells do not take up)
(2) antioxidants (oxidized LDLs in endothelial cells are bad)
alcohol in moderation (but people who die of cirrhosis rarely have
atherosclerosis)
statins (box on p. 412):
(a) block rate limiting step in cholesterol synthesis in liver
(b) secondarily increase LDL receptors
Readings
S. Cohen J Leor Rebuilding broken hearts, Scientific American, November 2004,
44-51
infarct kills cardiomyocytes
noncontractile fibrous cells replace
adjacent healthy myocytes may die
(remodeling)
ventricle wall becomes thinner, distends, might rupture
heart failure
tissue engineering - must have scaffold for cells and blood supply
3-D sponge-like frame made alginate (from algae) frozen
progress so far- can prevent further damage
add controlled release microspheres of growth factors to help angiogenesis
Pacemakers (keep the beat) [working knowledge] M Fischetti, Scientific
American, November 2004
wires run in through vein
tips have steroid reservoir to block early inflammation
that keeps contacts healthy
ICD - Implantable cardioverter defibrillator
Exam questions from 2004 - 2008 that relate to this outline:
When, in the heart cycle, do the bicuspid and tricusid valves snap shut?
at the beginning of ventricular contraction
What kind of blood vessels have the highest TOTAL cross sectional area?
capillaries
What does the last Korotkoff sound signify?
the diastolic (arterial) blood pressure
What are the cells that line blood vessels including capillaries called?
endothelial cells
Why is the wall of the ventricle thicker than the wall of the right ventricle?
systemic circulation is higher pressure than pulmonary
What is Einthoven's triangle?
Hook-ups for diagnostic EKG Leads I, II, and III on 2 wrists and left ankle
Long QT Syndrome, diagnosed by a lot of time between the QRS and the T, affects
a channel (for what ion?) involved in the repolarization of ventricular
myocardial cells?
K+
Cells in what areas depolarize automatically during diastole?
SA node
Although the electrical signal would pass from one myocardial cell to the next,
specialized fibers hurry it to much of the ventricular muscle synchronously.
What are these fibers?
bundle of His, bundle branches, Purkinje fibers
Why would you die of if there were too much time between heart failure and
defibrillation without CPR (cardio-pulmonary resussitation)?
brain would die without O2 (and glucose)
The time between the QRS and the T represents the duration for what specific
cell type?
ventricular myocardial cell
For a normal person, slow Ca2+ channels would control heart rate in which specific
part of the heart?
SA node
In good health, what part of the body clears LDL (and HDL) from the blood
stream?
liver
How does nitroglycerine help to relieve angina pectoris?
relax artery smooth muscle
What is the likely mechanism that antioxidants might prevent heart attacks?
oxidized LDL is bad
Why isn't an atrial beat needed for most of the venous return to go to the
ventricles during diatole?
tricuspid and bicuspid valves are open
What does the endothelium line?
blood vessels
If you took statins, what substance would decreased?
cholesterol
How do gap junctions contribute to heart function?
get action potential from one cell to another
Since there is not much blood pressure left, what is needed to help blood flow
along in veins?
valves
Taking blood pressure, you inflate the cuff to 180 mm Hg, then lower it. You
hear nothing until the systolic pressure is reached. After the diastolic
pressure is passed, you hear
nothing. Why do you get sounds only between systolic and diastolic pressures?
turbulent
What causes the second heart sound at the end of systole?
semilunars snap shut
How does aspirin help to prevent heart attacks?
inhibits platelet aggregation
Where does the vena cava (superior and inferior) empty into?
right atrium
At the moment the semilunar valves open, what is the blood pressure in the left
ventricle?
same as arterial diastolic
What is the function of an arteriovenous anastomosis?
shunt blood from peripheral vascular bed
What is the endothelium?
cell lining of blood vessels
What is a heart murmur?
a leaky valve
Compare the duration of the isovolumetric portion of the ventricular
contraction for someone with high diastolic blood pressure with that for a
normal person.
the ventricle would contract further before forcing open the valves to arteries
(for high b.p.)
What regulates the precapillary sphincter?
the sympathetic nervous system
"CN" in "HCN channels" stands for "cyclic
nucleotide." What do cyclic nucleotides have to do with pacemaker cells?
adrenergic receptor affects cAMP level
Explain the interval between the QRT complex and the T wave in terms of the
shape of the myocardial action potential.
that is a long action potential, QRS is depolarization, T is repolarization
How could you get a heart beat if there were no trigger from the SA node?
Eventually the AV node would kick in
At the moment of the last Korotkoff sound, what does the pressure dial show?
diastolic b.p.
What are baroreceptors in the carotid sinus used for?
regulate b.p.
In addition to increasing contractility, what does sympathetic input to the
heart do?
regulate heart rate
What is ischemia?
interuption of blood flow and hence oxygen supply
What does a defibrillator do to save your life?
starts heart again, makes it so SA node triggers heart
What does a high HDL/LDL ratio in your blood test results imply?
less risk for coronary artery problems
As opposed to apoptosis, what is the damage to cardiomyocytes in a heart
attack?
necrosis
What is it called when you have pain in parts of your body, like your left arm,
in a heart attack?
referred pain
What is a thrombus and why is it potentially damaging?
a blood clot that clogs the artery
What event occurs at the end of the isovolumetric contraction of the left
ventricle?
Aortic semilunar valve opens
Why do veins need to have valves to ensure forward blood flow while arteries do
not?
there is no blood pressure driving the blood
In what way does the Frank-Starling law differ from the striated muscle's
length-tension curve?
FS-More stretch (ventricular filling) more contraction, striated weaker when
muscle is long
Why is the first part of the ventricular contraction isovolumic?
Bicuspid and tricuspid are closed, semilunars do not open until ventricular
pressure > arterial
Heart cells die by cell damage, rather than by programmed cell death
(apoptosis). What is the term used for this kind of damage?
necrosis
A blood test shows that a patient has a high HDL to LDL ratio. What does this
mean?
these are good numbers re artery health
In an arteriole, what would a precapillary sphincter do under the influence of
the autonomic nervous system?
open or close to regulate blood flow to the capillary bed
What valves close right at the start of ventricular contraction?
tricuspid and bicuspid (atrioventricular)
Hyperpolarization cyclic nucleotide (HCN) channels are important in pacemaker
cells. Name the relevant and famous cyclic nucleotide, the one controlled by
beta-1 adrenergic receptors.
cAMP
In atria, the action potentials are passed from one myocardial cell to the
next. Why are there additional fibers (bundle of His, bundle branches, and
Purkinje fibers) for ventricles?
to speed the action potentials to the base
Parasympathetic fibers slow the SA and AV nodes below their rate of
automaticity. What nerve is this?
vagus, 10th cranial
Above the systolic pressure and below the diastolic pressure, you hear nothing.
Why are there Korotkoff sounds between systolic and diastolic pressure?
blood flow is turbulent
What does the Wiggers diagram tell us about the opening of the aortic semilunar
valve when the diastolic blood pressure is high?
ventricular pressure would have to be higher to push open the valve
Give an approximate value for the blood pressure in the ventricles during
diastole.
zero
What symptom would be noticed if the heart muscle were to attempt anaerobic
metabolism?
pain (angina)
What do aspirin, coumaden and the rat poison WARFarin have in common?
they inhibit coagulation
Valves between where and where snap shut at the beginning of ventricular
contraction?
atria and ventricles
For part of the heart cycle, ventricular and arterial pressures are equal. How
do these two pressures relate the rest of the time?
in diastole, ventricular is lower than arterial
What holds shut the aortic and pulmonary semilunar valves during the beginning
of ventricular contraction?
arterial pressure
In addition to the automatic tissues (predominantly SA & AV nodes) to what
does the sympathetic nervous system connect and why?
heart muscle to increase contractility
Electrically, what do pacemaker cells during diastole?
depolarize
How come the electrocardiogram can reach as far as the wrists and ankles for
recording?
virtually no extracellular resistance
What would happen to the time between Q and T waves with sympathetic
activation?
shorten
What is the difference between a thrombus and an embolism?
thrombus clot forms locally, embolism dislodged from elsewhere and arrives at
trouble spot
Why would a large area of damage in the heart lead to re-entry of excitation?
the distance from cell to cell to cell would have the spike arriving after the
refractory period is over
What type of cell is used for continuous and fenestrated capillaries?
endothelial
What is it that may shunt blood from arteriole to venule to bypass capillary
bed in the skin?
arteriovenous anastomoses
In what way is heart muscle different from striated muscle with respect to
strength as a function of length?
Frank Starling law has it that fuller (more stretched) ventricle has higher
contractility, while striated muscle tension drops off
As cuff pressure is being released, between the systolic blood pressure and the
diastolic pressure, your figure indicated that you get "sounds at every
systole." Why?
turbulent blood flow
How would nitroglycerine help if you felt a heart attack coming on?
relax smooth muscle in artery
Describe referred pain as it refers to heart attack.
projected to neck, arms
What is it that makes the bicuspid and tricuspid valves close to make the first
heart sound ("lub")?
pressure in the ventricles closes these atrio-ventricular valves
Why might a person pass out if (s)he stands without moving for a long time?
muscular contraction contributes to venous return, hence venous pooling
What part of the nervous system would regulate the precapillary sphincter?
sympathetic
During ventricular systole, just when the pressure forces the aortic semilunar
valve open, what is the arterial blood pressure?
equal to the diastolic pressure right then
About what fraction of ventricular filling is from the beat of the atria?
a very small amount, the figure shows about 10 out of 80 ml
What happens to the brachial artery when the blood pressure cuff is first fully
inflated?
it is completely closed
Suppose your SA node failed to fire. You would probably still have a heartbeat
(how?) and it might be reasonably adequate (why?).
AV node would fire, see q 10, most of the ventricular filling does not rely on
atria
What happens to the electrical potential of a cell in the sinoatrial (SA) node
during diastole?
there is diastolic depolarization in these pacemaker cells until threshold is
reached
How do we get recordings from 3 different "leads" in Eindhoven's
triangle starting with a positive electrode connected to one wrist, a negative
electrode connected to the other, and ground connected to an ankle?
The three so-called "leads" are gotten by swapping (2 at a time)
connections to the 3 locations
Before paramedics arrive with the defibrillator, why is cardiopulmonary
resuscitation essential?
CPR delivers enough oxygenated blood to the brain to keep it alive
"The bad news is that your cholesterol is high. The good news is that your
ratio is good." What would be a good ratio (when the cholesterol level is
broken down into its components)?
If HDL/LDL is high
At the peak of systole, how does the pressure in the right ventricle compare
with the pressure in the left ventricle?
Way lower pressure in pulmonary circulation
Both branches of the autonomic nervous system (sympathetic and parasympathetic)
connect to both nodes of the heart(SA and AV). In addition, the sympathetic
nervous system also makes additional connections to the heart (to where? Or for
what purpose?).
to muscle to increase strength of contraction
What would happen to the Q-T interval during strenuous exercise?
shorten
What is the function of an arteriovenous anastomosis?
Shunt blood to bypass capillaries in skin to prevent heat loss
this page was last updated 7/1/09
**The respiration lecture
RESPIRATION
Fox Chapter 16
"Plumbing"
TRANSPARENCY (review from introductory course)
Summarizes much of what will be said below, including the next transparency.
Nasal - moisture (smell) sniffing
Pharynx - larynx
Vocal cords larynx (laryngitis) "voice box"
Equal time to creationism : "Adam's apple"
Further down cilia sweep mucus, bacteria, dust up
(histology picture
of cilia)
Cilia sweep from pharynx to esophagus (where you can swallow "crud")
Smoking paralyses ciliary sweep (more crud, less sweeping, famously asbestos is
worse in smokers)
Fig. 16.4
Trachea - rings of cartilage to hold tube open like a vacuum cleaner hose
2 bronchi
Inflammation of the bronchi is called bronchitis.
Review chapter 9 material and note that sympathetic n.s. causes relaxation of
smooth muscle (opening passageways) in lungs and parasympathetic n.s.
constricts them (closing passageaways). The purpose is to regulate air flow.
Asthma caused by mast cells and eosinophils secreting leucotrienes,
bronchioconstriction, use epinephrine to stimulate beta 2 receptors (note heart
has beta 1 receptors). Epinephrine was in inhalers. Terbutaline is an anti beta
2 drug. Singulair is an antileukotriene. Because inspiration helps to open the
bronchioles, breathing out (this is counterintuitive) is most difficult.
Alveoli 600 million in human 50 x skin area
Here is a picture
from our histology course
(like Fig. 16.18) showing how thin the cell layers of alveoli are.
Fig. 16.17
Emphysema - alveoli merge, often results from smoking, increased muscular
effort in breathing- smoetimes they have a hunch back from using back to help
breathe. These are the people older than they look pulling a dolly of oxygen
around with them.
Fig. 16.20
[much like part of the figure from introductory course]
Air sacs (alveoli) are close to capillaries.
Note, red vs blue for arteriole vs venule is reversed for pulmonary
circulation, obviously.
Recall, pressure lower in pulmonary circulation, and there is no regulation of
flow to different areas as there is in systemic circulation.
Air Pressure
Fig. 16.18
Atmospheric pressure is measured in mm Hg
Fig. 16.19
Partial pressures of inspired air and alveolar air
Pressure relates to gas exchange.
In alveoli, H2O & CO2 higher and O2 lower for obvious reasons that we will
chat about.
Fig. 16.22
Here is the cardio-respiratory system with blue blood (P O2=40, P CO2=46) and
red blood (P O2=100, P CO2 = 40)
Lung volumes
Fig. 16.15 also here
Breathing in and out normally is called tidal breathing, volume about half a
liter. There is an expiratory reserve, over a liter, and an inspiratory
reserve, maybe 3 l. From the top of inspiration to the bottom of expiration is
vital capacity. Even after you empty your lungs as much as possible there is a
residual volume, over one liter.
A simple spirometer
with a dispo tube to breathe into can be used cheaply to measure vital
capacity, tidal volume and expiratory reserve.
A summary point: not all the air exchanges!
Ventillation
Fig. 16.7
Pleura, very slippery, and pleural cavity, slightly lower than atmospheric
pressure, are important.
Pleurisy is inflammation of pleura, breathing is painful.
The low pleural pressure keeps the lungs open unless an injury lets air into
cavity, "pneumothorax," collapses lung.
Fig. 16.14
Inspiration - pressure in lungs is lower than atmospheric, obviously, a word I
seem to be using often, and expiration, pressure is higher.
Fig. 16.13
Muscles involved: intercostals and diaphragm mostly, and others as well.
Subtle differences for inspiration and expiration.
Fig. 16.11
Water's surface tension would tend to collapse (close) alveoli. Type II
alveolar cells secrete surfactant (surface active agent), phosphatidylcholine
plus phosphatidylglycerol, that decreases surface tension. RDS (respiratory
distress syndrome) aflicts premature babies since surfactant production does
not start until late.
Cystic fibrosis is from mutation in CFTR (cystic fibrosis transmembrane
regulator), a chloride channel, results in viscous mucus.
Control of ventillation
Introduction: The receptors that are sensitive to changes in the concentrations
of CO2 and H+ are located within the arterial system and the medulla of the
brain. Excitation of these receptors trigger neural reflexes which alter the
respiratory rate and depth. Additionally, other parts of the nervous system
influence the basic ventilation pattern established by the respiratory center.
Fig. 16.24
Medulla rhythmicity center generates rhythm
Input from Pontine apneustic center (inspiration). Have you heard of sleep
apnea?
Input from pontine pneumotaxic center counteracts inspiration.
Fig. 16.25
There are chemoreceptors in the aortic and carotid bodies, go to medulla in
vagus (X) and glossopharyngeal (IX) respectively.
Fig. 16.26
This diagram adds a few items:
(1) Cerebral cortex over-rides. The funny thing about this information is that
it is hard for you to think about how you breathe without you changinging how
you breathe.
(2) There are important chemoreceptors in the medulla.
Fig. 16.28
Without the buffers that blood has, cerebrospinal fluid (CSF) on the other side
of the blood brain barrier has CO2 and H2O -> carbonic acid generating H+
that affects receptors.
Summary. A common misconception is that variation in the O2 levels within the
system cause changes in the ventilation rate. Actually, the O2 concentration,
under normal conditions, has little to do with the determination of respiratory
rate. The critical determining factor is the level of CO2 and/or the level of
free protons circulating in the blood. For example, an increase in CO2 or H+
levels will induce changes which result in an acceleration of the ventilation
rate and volume until these levels return to the normal range. Conversely,
conditions associated with alkalosis and lower than normal CO2 levels depress
the ventilation rate.
CO2 and CSF acidity are stimuli for breathing, and that is why oxygen given to
patients has CO2 in it.
Fig. 16.28
Decreased breathing increases CO2 etc., resulting in a compensatory (there's
that old negative feedback again) increase in breathing.
Fig. 16.27
Hyperventillation - blow off CO2 and desire to breathe less, can hold breath.
Transport of O2 and CO2
Fig. 16.31
The trouble is that oxygen does not dissolve well in water, 66 x as much oxygen
is in blood, with its hemoglobin, than in plasma.
Fig. 16.32
Everyone should know that hemoglobin is composed of 2 alpha chains, 2 beta
chains, and heme with iron in it.
Fig. 16.33
Here is the famous oxyhemoglobin dissociation curve, % oxyhemoglobin saturation
as a function of P O2 (mmHg).
By comparing arteries with veins, we can see how much oxygen is offloaded to
tissues.
Fig. 16.37
Importantly, hemoglobin will offload oxygen to myoglobin based on the
displacement.
(The same is true for the relation of adult hemoglobin and fetal hemoglobin.)
Fig. 16.38
From tissue to blood:
CO2 transported as bicarbonate, bound to hemoglobin, and dissolved in blood
CO2 dissolves better than O2 in water
Red blood cells CO2 + H2) -> (carbonic anhydrase)-> H2CO3 (carbonic
acid).
then H2CO3 -> H+ and HCO3- (bicarbonate)
When this diffuses out of RBC, Cl- goes in (chloride shift)
Fig. 16.39
The reverse happens to put CO2 from blood to alveoli.
Exam questions from 2004 - 2008 relating to this outline
If you hyperventillated, what would become of the pH of the cerebrospinal
fluid?
less CO2, pH goes up
What is the biological word for the Adam's apple?
larynx
Expiratory reserve plus inspiratory reserve plus tidal volume equals what?
vital capacity
What is the chloride shift?
Cl- goes into erythrocyte when HCO3- comes out and vice versa
What is the intrapleural pressure? (I want an approximate value.)
slightly less than atmospheric
What two gasses have much higher partial pressure in alveolar air than in
inspired air?
H2O, CO2
What are the pneumotaxic center and the apneustic center used to control?
respiratory rhythm
Cystic fibrosis is a channel for what ion?
Cl-
An asthma spray would contain an agonist for what naturally ocurring
neurotransmitter?
norepinephrine
Where are the brain centers that control breathing?
medulla and pons area
The abscissa (X-axis) of the oxyhemoglobin dissociation curve is partial pressure
of O2 in mm Hg. What is plotted on the ordinate (Y-axis)?
% saturation (with O2) of hemoglobin
What compound (related to but not the same as prostaglandins) constricts
bronchial smooth muscle (blocked by Singulair)?
leukotriene
One reason that the partial pressure of CO2 is higher in alveoli than in the
atmosphere is that cells generate CO2 (as waste). What is the other reason?
not all the air in the lungs is exchanged by breathing
Partial pressures for CO2 and O2 are almost equal in alveolar air and pulmonary
veins. For which gas is there a greater difference between alveolar air and
pulmonary arteries?
O2
Which component of lung volume cannot be measured with a spirometer?
residual volume
What is the naturally ocurring hormone for beta-2 receptors in bronchi?
epinephrine
What is the highest level that mercury would rise in a glass tube with a vacuum
at the top?
760 mm
Respiratory distress syndrome in premature infants results from the lack of
what molecule?
surfactant (phosphatidyl choline)
Where do chemoreceptors in aortic and carotid bodies feed to to control
breathing?
medulla
What would alkaline cerebrospinal fluid do to breathing?
inhibit it
In pneumothorax, what compartment increases its pressure to that of the
atmosphere?
intrapleural
In addition to containing heme, how would you describe the molecular structure
of hemoglobin?
2 alpha and 2 beta protein chains
A figure in your text indicated that one place was responsible for
"automatic breathing," while I cautioned you that this was very
different from automaticity in the heart. What is this place that generates
automatic breathing?
Medulla
Bicarbonate in plasma helps in CO2 transport. It is made with the help of what
enzyme in what cell?
carbonic anhydrase in red blood cell
What would O2 on mother's hemoglobin do when it gets near fetus hemoglobin in
the placenta?
offload to fetal
When is the pressure in the alveoli slightly higher than atmospheric?
expiration
The total lung capacity is tidal volume + inspiratory reserve + expiratory
reserve + what?
residual volume
What is the significance of the value 760 mm Hg?
atmospheric pressure at sea level
Why does a mutant chloride (Cl-) channel (CFTR specifically) lead to lung
disease?
poor ion transport -> poor water transpord -> viscous mucous
For the sake of CO2 transport, where is bicarbonate (HCO3-) made and where is
it carried?
made in RBC, carried in plasma
Why is the partial pressure for alveolar H2O much higher than for H2O in
inspired air?
air is humidified, usually in nasal passageways
What common effect (though to different extents) do leukotrienes and the
parasympathetic nervous system have on bronchioles?
decrease air flow
What does emphysema do to the number of alveoli?
decrease since adjacent ones merge
Why is the partial pressure for CO2 higher in the pulmonary artery than in the
alveoli?
pulmonary artery carries CO2 offloaded by tissue respiration
Although phosphatidylcholine is best known as a membrane phospholipids, it also
has a special function in the lungs. What is this function.
component of surfactant, decrease surface tension of water
You breathe in and out your vital capacity a dozen times in rapid succession.
What is this called and why would your urge to breathe be decreased for the
next minute?
hyperventillation, by blowing off CO2, less H+ in medulla
A stab wound to the chest can lead to the collapse of a lung because what
compartment would increase its pressure to atmospheric pressure?
intrapleural space
What is the important nerve connecting the heart and the brain that carries
chemoreceptive signals from the aortic bodies?
vagus (10th cranial)
Why would you want to inhale adrenalin? (Your answer can address pathology,
cells or molecules.)
asthma, relax smooth muscle, open bronchial airways, activate beta 2 adrenergic
receptors
Why is the partial pressure of oxygen lower in alveoli lower than in the
outside air?
because water vapor and carbon dioxide fractions are so much higher
A slight increase in pressure (where?) would allow the lung to collapse if
there were a stab wound to the chest?
intrapleural space
Why would asbestos be more likely to stay in the lungs of smokers than of
non-smokers?
smoking paralyses cilia
How does intrapleural pressure relate to alveolar pressure (at rest, breathing
in and breathing out)?
a little lower in all cases
Why would it take more effort than a premature baby could muster to breathe?
there is no surfactant to decrease water tension
Name one of the two nerves that carry chemosensory input to the brain to
control respiration?
glossopharyngial (9th) and vagus (10th)
Why is it so useful to monitor pH of the cerebrospinal fluid to report the need
to breathe?
carbon dioxide would make pH go down
What does the sympathetic nervous system do in bronchi? (Your answer can either
be at the level of the cellular response or of the passageway function.)
beta 2 receptors relax smooth muscle open airway
What could you do to lower the partial pressure of carbon dioxide in your
alveoli?
hyperventillate
Give a ballpark figure for the partial pressure of carbon dioxide in the
arteries for normal breathing and for hyperventilation.
40 mm Hg, less if hyperventillate
Why does chloride need to go in and out of red blood cells?
to move bicarbonate to plasma where there is room to carry it
Why wouldn't you expect inhibitors of prostaglandin synthesis to help with
inflammation in asthma?
Leukotrienes, not prostaglandins
Total lung capacity minus expiratory reserve minus inspiratory reserve minus
residual volume equals what?
Tidal volume
What happens to the pressure in what compartment to cause the lung to collapse?
Intrapleural becomes equal to atmospheric
Other than the medulla (of the brain), where are there chemoreceptors to
control ventilation? (or, if you prefer, tell me how they feed to the brain.)
aortic and carotid bodies
What is the purpose of cilia in the trachea?
to sweep gunk captured in mucus up to where it gets swallowed
How would epinephrine in an inhaler affect breathing? (Your answer could apply
to molecular type of the receptor or to affect on the airway.)
beta 2, dilate (open) bronchioles
What is it that would make mercury go up 760 mm in a glass tube?
atmospheric pressure (not "suction")
Give at least 2 reasons oxygen's partial pressure is so much lower in alveoli
than in the atmosphere.
our of 3: (1) there is so much CO2 in alveoli, (2) there is so much H2O in
alveopi, (3) not all air is exchanged each breath
The partial pressure for carbon dioxide in the pulmonary artery is 46. What is
it in the pulmonary vein?
lower, but not that much lower (40)
Why would they put premature babies in high oxygen?
lack of surfactant makes breathing difficult
Relative to carbon dioxide, how much oxygen is carried in the plasma?
O2 is way less soluable in water than CO2 (the figure clearly showed 10% for
CO2, another figure implied about 1.5 % for O2)
"Most bicarbonate is carried in the plasma." But it was made in the
erythrocyte. What trickery was used to move it to the plasma?
exchange with Cl-
this page was last revised 7/9/09
**The kidney lecture
Excretion and
homeostasis
Fox Chapter 17, one figure from Chapter 6
How the kidneys function is way more interesting than you may have thought.
Summarizing, they throw the baby out with the bath water, then recover most of
it.
Consider the work of the kidneys
Artificial kidney (dialysis) 10 hr 2 times per week
This is why transplant important, and there is difficulty getting a compatable
donor.
Cell makes wastes that go into the plasma.
Heart pumps 7000 l/day (32 55 gal drums).
1/4 (8 55 gal drums) through kidneys
Glomerulus - Bowman's capsule passes (filters) 180 l/day.
And yet only 1 l of urine is produced per day.
Osmoregulation (for ions)
Review:
Hypertonic (concentrated), isotonic, hypotonic (dilute).
Nitrogenous waste (urea) is from catabolism of amino acids and nucleotides.
Ammonia (toxic) would be o.k. for small water animals where it can diffuse
away.
Comparative biology
There is a tradition in undergraduate biology to emphasize comparative aspects:
Malpighian tubule in insects puts out uric acid and rectum recovers water and
other molecules.
Uric acid is used in birds, reptiles, and insects, and water loss is minimized
The nitrogen story
Although 78% of the atmosphere is nitrogen in the form of N2, this is fairly
unreactive.
Thus there are these important processes: N2 to NH3 nitrogen fixation, NH3 to
NO3- (nitrate) nitrification, NO3 to NH3 (nitrate reduction) in plant roots.
Also nitrogen is recycled.
In Pacific, off the coast of Peru, the Humbolt current causes an upwelling of
nutrients, anchovies thrive, bird droppings (guano) were used as fertilizer.
El Nino (the Child, named not for misbehavior but because it comes near
Christmas) is a periodic climate misbehavior that disrupts this.
The uric acid story
In humans, mild accumulation of uric acid causes gout - crystals in joint cause
inflammatory response which is treated by NSAIDS (non-steroidal
anti-inflammatory drugs like prostaglandin inhibitors like indomethacin,
ibuprophin, and aspirin). Enzyme is inhibited by chronic treatment with
allopurinol. Genetically pathological uric acid accumulation which is
Lesch-Nyhan syndome - children have bizarre self mutilation from HGPRTase
(hypoxanthine guanine phospho ribosyl transferase) deficiency.
Functional anatomy
Fig. 17.1
kidney, ureter, bladder, urethra
Fig. 17.2
Kidney
Pelvis=basin; Medulla=marrow; Cortex=bark ("medulla" and
"cortex" are terms used a lot, like in brain and in adrenal gland)
The blood supply is huge (1/4-15 of body at rest) and regulated (way less in
stress)
Renal artery and vein branches near eachother
each kidney has 1 million nephrons:
Capsule, PCT, loop of Henle, DCT, collecting duct (this will be repeated in
other figures)
Filtration
Fig. 17.5
Blood flow in glomeruli
Notice "afferent" (toward) and "efferent" (away from)
arterioles, implies a portal system to next capillary bed iaround nephron and
in medulla
Fig. 17.13
Glomerulus - Bowman's (glomerular) capsule
I picked just one figure, when the book uses several to develop the point
gradually.
Blood pressure and osmotic pressure drives sieve
Green is protein that is too big to fit through.
Blue is all small molecules.
Na+ is actively transported, Cl- and H2O follow
Fig. 17.7
Fig. 17.9
Glomerulus - fenestrae (windows) in capillaries and slits between podocyte
pedicels make up sieve.
here is a
picture from the histology
course
another picture
highlights glomerulus by dye injected into artery
large molecules dye do not pass
- small molecules dye passes through
blood proteins and cells do not pass
urinalysis strips
test if blood, cells or protein is present
Clearance test for filtration
Fig. 17.22
One test of kidney function, specifically filtration, is inulin clearance test
Inulin is an injected dye that is filtered but not resorbed.
Short of injecting inulin, an endogenous molecule, creatinine, can be assayed.
Resorption of glucose
Fig. 17.24
Proximal Convvoluted tubule - bring back amino acids, glucose note active
(NaCl) vs passive (water) transport
Glucose is a special case.
(1) ATP is used in a Na+-K+ pump on basolateral cell surface
(2) glucose is cotransported with Na+ on apical cell surface
(3) Cells are joined so there are no other pathways
(4) recovery in capillary is by diffusion
Why an untreated diabetic has glucose in the urine is that this mechanism is
saturated and cannot recover all of the glucose filtered from high blood
glucose.
Resorption of salt
Kangaroo rat - metabolic water, hypertonic urine
Fig. 17.15
Ascending loop - salt resorbed but not water
Ascending loop of Henle - salt outward resorption is stimulated by aldosterone
Some passive water recovery is made possible because of high tonicity of
interstitial fluid in the medulla.
This is called the countercurrant system
Fig. 17.18
A summary shows dilute in cortex, hypertonic in medulla
Secretion
Fig. 17.21
Kidney also secretes - pump out (penicillin)
Hormonal control
TRANSPARENCY (from an intro book)
ADH (vasopressin) makes water follow back into interstitial fluid which is
hypertonic from salt
alcohol and caffeine inhibit ADH, hence diuresis (excessive urination)
affects water channels called aquaporins
Fig. 17.20
regulation of ADH by negative feedback (from hypothalamus to pituitary) and
relation to thirst and water intake
Fig. 6.14
This same concept was covered way back in Chapter 6.
The relation of thirst to water conservation via ADH
Fig. 17.26
low blood pressure -> JGA (juxtaglomerular apparatus) makes renin
Fig. 17.27
Renin causes Angiotensinogen (liver) -> angiotensin II- closes arterioles
stimulates aldosterone
High blood pressure ->atrial natriuretic protein ->(-) aldosterone and
renin
Sweat
Filter, resorb (salt and water)
Sweat pores not as good -which is why gatorade tastes good to athletes
especially bad in cystic fibrosis (salty sweat) molecular genetics shows a
chloride channel defect
Exam questions from 2004 - 2008 relating to this outline
Blood arrives at the glomerulus for filtration. What do they call the blood
vessel that carries blood away from the glomerulus?
efferent arteriole
In addition to facilitated diffusion at the basolateral cell surface, what is
necessary for glucose transport in kidney tubule and intestinal cell? (Include
process and location.)
apical cotransport with Na+
What is the product of the juxtaglomerular apparatus?
renin
High levels of what nitrogen-containing chemical cause gout?
uric acid
Why are alcoholic beverages contraindicated to stay hydrated in times of heat
stress? (Make sure your answer says what happens to the relevant hormone
level.)
alcohol inhibits ADH, more water is lost through kidney
Cystic fibrosis is a channel for what ion?
Cl-
Where are the cell bodies of the cells whose axon terminals release ADH and
oxytocin?
hypothalamus
What does creatinine clearance test for?
glomerular filtration
In the intestine and the kidney tubule, three processes are needed for glucose
transport, (1) basolateral sodium pump, (2) basolateral facilitated diffusion,
and (3) apical... [your
turn].
glucose/sodium cotransporter
Because of the portal system, the vessel carrying blood from the glomerulus is
not called a vein. What is it called instead?
efferent arteriole
If a kidney stone passed from the kidney to the bladder, what tube would it go
through?
ureter
What accumulates in Lesch-Nyhan syndrome?
uric acid
By what mechanism are proteins excluded from the primary filtrate in the
kidney?
size of sieve openings (podocytes and fenestrated endothelium
Why might you give a secretion blocker in conjunction with penicilin?
keep antibiotic from being pumped out by kidney
Why do cells in the proximal convoluted tubule need to pump sodium to reclaim
glucose?
because of sodium-glucose cotransporter ion apical surface
In what tube does the final, ADH-dependent, water reclamation occur?
collecting duct
Instead of injecting inulin, what test is there for clearance assaying for a
substance already in the body?
creatinine
Renin activates what hormone?
angiotensin II
In the kidney tubules, salt and water are reclaimed. Only one substance is
actively transported. What substance? (Be specific.)
sodium
What hormone from the adrenal cortex is essential for salvaging salt in the
kidney?
aldosterone
There is a capillary bed in the glomerulus. Where is the other capillary bed of
this portal system?
medulla
Na+, Cl- and H2O are all recovered in the proximal convoluted tubule. Which
involve active transport?
Na+
Aquaporins in the collecting ducts are regulated hormonally. What are
aquaporins?
ater channels
At what location in the lumen of the kidney tubules is the tonicity the
highest?
loop of Henle (and maybe deep collecting duct)
Describe either how the kidney deals with inulin or, alternatively, what
specific aspect of kidney function inulin is used to test.
filters but does not retrieve, tests GFR=glomerular filtration rate
Considering how unreactive nitrogen gas (N2) is, how did it get into biological
molecules such as amino acids?
nitrogen fixation
The glomeruli vs. the loops of Henle are in which two overall anatomical
portions of the kidney respectively?
cortex, medulla
In addition to the fenestrations in capillaries, what cellular architecture is
responsible for glomerular filtration?
pedicels of podocytes
What change in appetite would occur if the adrenal glands were removed?
you would crave salt
What is detected by the juxtaglomerular apparatus that makes these granular
cells release their renin?
pressure in afferent arteriole
If you drink very little and become thirsty, what pituitary hormone would be
increased?
ADH=antidiuretic hormone
What are creatinine and inulin reapectively and what are they used for?
creatinine is already in body and inulin is injected, buth used to test
glomerular filtration since they are filtered but not resorbed
For glucose in the kidney, tell me the surface locations of the three
transporters involved.
cotransport apical, basolateral facilitated diffusion plus sodium pump
What should happen to the tonicity of urine if a drug that inhibits ADH
(antidiuretic hormone) were administered?
becomes dilute
Why are drugs like aspirin called prostaglandin inhibitors?
they block synthesis by blocking the cyclooxygenase (COX)
What is the tube that connects the kidney with the bladder?
ureter
What do they call the blood vessel exiting the capillary bed that is in the
glomerulus?
efferent arteriole
Salt and water are recovered in the proximal convoluted tubule. What is active
and what is passive? Be specific.
sodium ion active, chloride and water passive
Why would a rat drink salty water after an adrenalectomy?
aldosterone which favors salt recovery would be missing
Where, in the nephron's components, are the aquaporins that are influenced by
ADH (antidiuretic hormone)?
collecting ducts
What does the juxtaglomerular apparatus monitor and why is it in a good
location to do this job?
blood pressure, near afferent arteriole
From the renal pelvis, the urine flows to the bladder via what tube?
ureter
Why is it advantageous to have hypertonic interstitial fluid in the kidney
medulla?
Then, if ADH is present, water will be salvaged from the collecting duct
Why would it be advantageous to position renin secreting cells where they are?
Blood pressure is monitored near the glomerulus for the emergency work of
angiotensin that rennin initiates
Drugs that inhibit prostaglandin synthesis might help with the symptoms of
gout. Why?
b/c it is the inflammatory response to the uric acid in the joint that is pain
What is wrong in Lesch-Nyhan syndrome children (HGPRTase deficiency)? (Your
answer can be behavioral or chemical.)
self-mutilation, uric acid accumulation
What blood vessel connects the two capillary beds of the nephron and hence
serves as the portal vessel?
the "arteriole" that is efferent from the glomerulus
Out of all the things a nephron does, inulin clearance tests for just one.
What?
glomerular filtration
How is glucose transported at the apical surface of the cell of the kidney
tubule?
apical is the co-transport with Na+
What would an adrenalectomy do a rat's specific appetites?
without aldosterone, there would be increased sodium appetite
What would inhibiting ADH do to the urine?
inhibiting antidiuresis, two negatives make a positive, so diuresis, more (and
more dilute) urine
this page was last updated 7/15/09
**The digestion lecture
Digestion
Fox Chapter 18, figures from chapters 4, 6 & 19
Chemistry
TRANSPARENCY (From intro bio)
Fig. 18.1
break down long chain proteins, polysaccharides and nucleic acids into monomers
recall hydrolysis (opposite of dehydration synthesis) (hydro-water lysis-break
apart)
if not broken down, proteins which are non-self would make a big antigen
invasion
TRANSPARENCY (From intro book)
Tube - Alimentary canal
Input - output
Fig. 18.2
One emphasis will be on how the human digestive system invests many juices
(hydrolases = enzymes which catalyse hydrolysis)
Some glands have ducts and these are called exocrine glands.
This is in contrast with endocrine glands (ductless, for hormones, which are
also involved in digestion)
800 g food IN per day
1200 ml water
/
/ 7000 ml GLANDS
/
50 g solid OUT
100 g water
Overall anatomy
(from mouth to stomach)
Mouth - teeth, lubrication, salivary amylase to disaccharide maltose - starch
tastes sweet (only starch in mouth)
-ase enzymes
Pharynx swallowing
Esophagus - bolus, peristalsis
Cardiac oriface
An integrative story
Rats cannot vomit (cardiac oriface cannot open for reverse peristalsis). They
are very good at learning, in one trial, to permanently avoid tastes which make
them sick. (You too may have developed a temporary dislike of foods you ate
before getting sick.) They can only be poisoned by chemicals with a delayed
reaction like Warfarin (warf = Wisconsin alumni research foundation) which is
an anticoagulant. (It is also used in lower doses to prevent heart attack
(coronary thrombosis).
Stomach
Fig. 18.5
Stomach - gastric mucosa - mucus protect
Fig. 18.6
from parietal cell: HCl kill bacteria
stop amylase
From chief cell: pepsinogen ---(HCl, pepsin))--> pepsin (proteolytic)
optimum pH for pepsin is 2
(Inactive forms called zymogens)
Heartburn, antacids, ulcer (although it is now known that a specific bacterium,
Helicobacter pylori, is associated with ulcer)
very little absorption in stomach - exceptions: aspirin, alcohol
Fig. 4.4
The optimum pH for pepsin (proteolytic enzyme in stomach) is acidic while for
trypsin (proteolytic enzyme in intestine) is slightly basic. And for salivary
amylase, it is neutral.
Fig. 18.5 again
Pyloric sphincter regulates emptying of acidic gastric juice to duodenum.
In duodenum, bile from liver and bicarbonate and enzymes from pancreas add to
enzymes from small intestine
Intestine:
enzymes - lactase, maltase, sucrase, others
mitosis - since cells digest themselves
absorption - food and water
Fig. 18.10
Villi (big) increase surface area. Note mitoses in crypts.
Here is a micrograph
from our histology course
dramatizing the tremendous increase in apical surface area of intestinal cells
caused by the microvillar brush border.
Signalling by G-protein involving cAMP (covered earlier) is disrupted by
cholera toxin - a life-threatening diarrhea, must replace fluids - salts and
glucose (as in the electrolyte coctails athletes drink like Gatorade)
facilitate water absorption
Fig. 18.12
The microvilli in the intestines have a special name, the brush border.
Protease (enteropeptidase turns trypsinogen into trypsin which, in turn, makes
chymotrypsin and carboxypeptidase (and others)
Fig. 18.33
How proteins are broken down and absorbed is complex.
Trypsin and chymotrypsin are endopeptidases.
Carboxypeptidase, exopeptidase, cuts carboxy terminal.
Aminopeptidase (shown on brush border) cuts amino terminal.
Di- and tri-peptidases are intracellular.
Intestinal cells digest themselves, and their enzymes go into intestinal lumen.
Fig. 6.21
how glucose gets absorbed
same story as for kidney, and, in fact, notice "lumen of kidney tubule or
small intestine"
apical, cotransport with sodium
basolateral Na+-K+ATPase plus glucose facilitated transport
Pancreas
Fig. 18.27b
Pancreas is responsible for dumping in many of the enzymes
Unit of this exocrine gland is the acinus
Zymogen refers to precursor of enzyme.
Table 18.4
"pro..." as in "procarboxypeptidase and "...ogen" as
in "chymotrypsinogen" --a peptide fragment is cut off from a larger
precursor protein to make active enzyme; there are many examples like this in
biology, for instance prohormones cleaved to make active peptide hormones.
Pancreas puts out bicarbonate (alkaline) to neutralize stomach acid.
Optimum pH for for trypsin is 8.
Fig. 18.25
Pancreas and common bile duct (from liver and gall bladder) dumping into
duodenum.
When I took organic chemistry lab (1966-7) we used gall stones for a
cholesterol extraction.
Note: Islets of Langerhans (endocrine tissue) in pancreas where alpha cells
make glucagon and beta cells make insulin.
Liver
Very few enzymes.
Emulsify fats.
Iron recycling.
Eliminate some wastes to feces.
Detoxify.
Detoxification
Portal blood veins (circulatory system "wired" in series is unusual,
another famous example being the hypothalamus of the brain which feeds to the
pituitary gland and kidney cortex to medulla). Via hepatic portal vein pick-up
from small intestine is first delivered to liver cels. There, "microsomal
fraction" (how biochemists view the smooth endoplasmic reticulum) has
enzymes to detoxify. Enzymes like those that detoxify drugs like barbiturates
are increased on exposure to toxins (inducible). Alcohol -(alcohol
dehydrogenase (ADH) )-> aldehyde - (aldehyde dehydrogenase)-> acetic
acid. With AcetylCoA, acetic acid can add to fatty acid chains 2 carbons at a
time. There is a fatty metamorphosis of the liver from one binge. Continued
heavy drinking leads to scarring and cirrhosis.
Fig. 18.22
Fig. 18.23
Erythrocyte iron recycling, bile pigment (bilirubin) ->urobilinogen turns
feces dark.
Also colors urine.
Hepatitis (disorder which spills bile into blood) - turns skin yellow
(jaundice) (feces are not as dark, urine is darker)
Fat digestion
Fig. 18.24
bile salts, salts of cholesterol, that emulsify fats
Fig. 18.35
Liver contributes to fat digestion
Fig. 18.34
Triglycerides are broken to monoglycerides and free fatty acids.
Fig. 18.36
Despite this breakdown, fats are reassembled, put in droplets with proteins and
carried in lymph duct called lacteal.
Hormones
Table 18.5
Local hormones control digestion - Many found later in other places
Fig. 18.30
from stomach:
food stimulates gastrin which, in turn, stimulates gastric juice until there is
a low (acidic) pH
from duodenum:
Cholecystokinin (CCK) - liver and pancreas
Secretin for bicarbonate release
Enterogastrones to slow gastric emptying
Appetite
It is worth mentioning that hunger and satiety are complex
In old work on brain lesions, LH (lateral hypothalamus) was called the hunger
center, while the VMH (ventromedial hypothalamus) was considered to be the
satiety center, but it never turned out to be so simple.
Hypothalamus is important in many motivated behaviors including thirst and sex
drive.
Affect (the aspect of perception of goodness or badness of a stimulus) is
linked through the nigrostriatal tract (bundle of nerve axons) which uses the
neurotransmitter dopamine and which is deficient in patients who have
Parkinson's disease.
Fig. 19.3
Now it appears that there is a hormone which is called leptin which is released
by (well-fed) fat cells which causes the brain to decrease apetite.
Specific appetite for salt after adrenalectomy eliminates aldosterone.
Recent literature
Leptin
JKElmquist & JSFlier, The fat-brain axis enters a new dimension Science
304, 63-64, 2004 (Perspectives)
SGBouret, SJDraper & RBSimerly, Trophic action of Leptin on hypothalamic
neurons that regulate feeding, Sci 304, 2004, 108-110
SPinto, AGRoseberry, HLiu, SDiano, MShanabrough, XCai, JMFriedman, TLHorvath,
Rapid rewiring of arcuate nucleus feeding circuits by leptin, Sci 304, 2004,
110-115.
ob/ob mice are leptin deficient
arcuate nucleus of hypothalamus
orexigenic, Neuropeptide Y (NPY) and agouti-related protein (AgRP)
anorexigenic, proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated
transcript (CART)
leptin regulates synaptic plasticity and axon guidance
Exam questions from 2004 - 2008 related to this outline
Loss of what hormone would cause an adrenalectomized animal to crave salt?
aldosterone
What is the function of the "microsomal fraction" in liver cells?
detoxify
Mitosis in the crypt of the villus is needed because of a short life expectancy
of which cells?
intestinal epithelial cells
Repeated fatty metamorphosis of liver from alcohol binges leads to what
scarring disorder?
cirrhosis
In addition to facilitated diffusion at the basolateral cell surface, what is
necessary for glucose transport in kidney tubule and intestinal cell? (Include
process and location.)
apical cotransport with Na+
What hormone from adipose tissue contributes to weight regulation?
leptin
The opposite of dehydration synthesis (condensation reaction) happens in
digestion. What is this called?
hydrolysis
What is the optimum pH for pepsin?
very acidic (2)
Recycling of what kind of cell contributes to the dark color of feces, the
yellow color of urine and the yellow skin in jaundice?
red blood cells
What is a zymogen?
inactive forms of digestive enzymes
Where does trypsinogen come from?
pancreas
Cholera toxin affects the level of what famous "second messenger" in
the intestinal epithelium?
cAMP
The portal vessel in the digestive system connects the intestine (where
absorption takes place) to that organ?
liver (its the hepatic portal vessel)
Jaundice is a symptom of a disorder of what organ?
liver
What is the function of cholecystokinin (CCK)?
hormone in digestion, slows gastric emptying, cranks up pancreatic secretions
What is the function of salts of cholesterol made by the liver and secreted
into the small intestine?
emulsify fats
In the intestine and the kidney tubule, three processes are needed for glucose
transport, (1) basolateral sodium pump, (2) basolateral facilitated diffusion,
and (3) apical... [your
turn].
glucose/sodium cotransporter
Cholera toxin interferes with water transport in the intestines in a mechanism
utilizing what famous "second messenger?"
cAMP
What is the name of the lymph vessel in the intestinal villus that is important
if absorption of fat?
lacteal
Many factors including hormones control gastric emptying via what
"valve?"
pyloric sphincter
When I was in first grade, we were told to keep a saltine cracker in our mouth
and notice that eventually it tasted sweet. What enzyme is responsible for
this?
amylase
You swallow a bolus, and it gets broken apart and mixed with lots of fluid.
What is the name of the fluid mixture emptying into the intestine?
chyme
What do you call the inclusions in pancreatic acinar cells with reference to
the fact that they contain precursors of enzymes?
zymogen granules
What is the name biochemists use for the smooth endoplasmic reticulum of liver
cells responsible for detoxifying toxins?
microsomal fraction
Where are the dipeptidases and tripeptidases responsible for the final
breakdown of proteins to amino acids in digestion?
inside the intestinal cell
If one glucose transporter is on the brush border, where (specific cell
surface) is the other?
basolateral
In a healthy person, what is the fate of bilirubin after it arrives at the
liver?
converted and out in feces
What is the source of the digestive enzyme that converts fats to fatty acids
plus a monoglyceride?
lipase is from pancreas
What does it mean to say a substance is orexigenic?
makes you want to eat
Where is the median eminence?
Where hypothalamus connects to pituitary
Argue that the effect of a hypothalamic lesion on weight regulation might
result from loss of affect by interrupting the nigrostriatal tract. Be specific
about what effect you are talking about and/or what part of the hypothalamus.
weight loss from lateral hypothalamus lesion might be from not appreciatng the
"goodness" of food
List one (of the several) effect of gastrin.
make parietal cell secrete HCl or chief cell secrete pepsinogen (or ECL cell
secrete histamine)
Why is a portion of the hypothalamus referred to as "supraoptic?"
it is above optic chiasm
In what molecular form is fat absorbed from the intestinal cell (to the body)?
triglycerides combined with protein in droplet called chylomicron
Name an enzyme derived from a pancreatic precursor that is an endopeptidase.
trypsin, chymotrypsin
What are zymogen granules in pancreatic acinar cells?
contain precursors of digestive enzymes like trypsinogen
"Enterokinase on the brush border cleaves trypsinogen to activate
trypsin." Translate.
the microvilli on intestinal epithelial cells activate the proteolytic enzyme
by cutting off a peptide fragment
What is the purpose of bicarbonate secretion by the pancreas?
neutralize stomach acid for intestine
"Proteins are hydrolyzed into singal amino acids to be absorbed by
intestinal epithelial cells and passed into the blood stream." Why is this
not the whole truth?
peptides of 2 and 3 aminoacids can be taken into cell for final breakdown in
cell
As heme is broken down, one of the products is bilirubin. What becomes of this
substance?
conjugated to gluconuride, converted to uropilinogen, put out in feces and
urine
The hepatic portal vein carries blood from the small intestine to where?
liver
What happens to a monoglyceride inside a cell of the small intestine?
two fatty acids added (converted to fat (triglyceride)
Gastrin stimulates secretions of parietal and chief cells. Name these
secrtetions.
HCl, pepsinogen
What would be the cause of death if you had cholera, and how might you prevent
death if you were nowhere near medical help?
dehydration, gatorade
What specialization in the stomach regulates gastric emptying into the small
intestine?
pyloric sphincter
"Leptin causes a decrease of the orexigenic neuropeptide Y from the
arcuate nucleus." Translate.
neuropeptide Y from that part of the hypothalamus would cause the opposite of
anorexia, so the protein leptin should be good for weight loss
Go on a drinking binge and there will be fat in the liver the next day.
Biochemically, how did that fat get there?
alcohol -> aldehyde -> acetic acid (adds 2 carbons to a fatty acid)
The same sort of drug given to heart patients to decrease the likeliness of a
thrombus is very useful as a rat or mouse poison. Why?
rats avoid tastes of foods that made them sick and anticoagulants work so
slowly that they never make the association
Bilirubin results from what ativity in what organ?
derived from red blood cell hemoglobin, handled by liver
What molecules make up the chylomicrons that are transported to the lacteal?
triglycerides plus proteins
Why are ob/ob mice obese?
lack leptin
What is the word for the coordinated wave of smooth muscle contraction that
propels a bolus of food forward through the esophagus?
peristalsis
Baking soda would be a quick fix for what digestive ailment?
"heartburn" caused by excessive stomach acid
The appropriate signalling that involves cAMP for water absorption in the
intestine is disrupted by what toxin?
cholera
After enzymes act on proteins in the intestinal lumen, list every product of
that degradation that gets absorbed into the intestinal cell.
single amino acids, dipeptides, tripeptides
Conversion to what molecule explains why alcohol consumption can cause fat
deposits in the liver?
acetic acid (acetyl coA)
"Gastrin stimulates parietal cells to secrete HCl." In parallel, it
stimulates chief cells to secrete what?
pepsinogen
Why might the nigrostriatal dopamine tract have to do with hunger/satiety?
contributes to motivation and affect
What indication of body energy stores would cause leptin to increase?
increased fat in adipose tissue
"Agouti-related protein (AgRP) is orexigenic." Translate.
this protein, oddly related to coat color, increases desire to eat
"The product of the parietal cells activates the product of the chief
cells." Elabortate.
parietal cell puts out acid which converts chief cell's pepsinogen into pepsin
Why do some people occasionally drink a spoonful of baking soda mixed in water?
baking soda = "bicarbonate of soda" = sodium bicarbonate, neutralizes
stomach acid, helps with "heart" burn
Away from emergency responders, what can you offer better than water to
rehydrate a cholera victim?
an electrolyte-glucose coctail such as Gatorade is absorbed better
The microvilli on the surface of the intestinal cells are so famous that they
have a name. What is that name?
Brush border
Why, in terms of chemistry or process involved, does hepatitis lead to
jaundice?
inflammation has hepatocytes spill bilirubin (from hemoglobin recycling) into
blood instead of feces
In terms of fat digestion, what is transported across the basolateral surface
of the intestinal epithelium into the lacteal?
chylomicrons are triglycerides bound to proteins
You were shown that amino acids stimulated the G cell to release gastrin which
caused the production of (what?) (also where?).
(via an intermediate ECL cell that releases histamine): acid in the stomach
"Agouti-related peptide (AgRP) is orexigenic." Explain to someone who
is not as sophisticated as you (are supposed to be) either: The meaning of
orexigenic. Or. How (in the heck) did we get on the topic of agouti?
opposite of anorexigenic, stimulating appetite. Although agouti has to do with
coat color, this protein which is orexigenic is like agouti, hence that
seemingly esoteric naming
For glucose absorption from the gut, what is the process on the basolateral
surface that requires energy?
The sodium pump
Sometimes endopeptidases will cut off fragments that are two amino acids long.
What becomes of these?
"In histology, you see zymogens located in acinar cells." What does
that have to do with digestion?
These granules house the precursors of digestive enzymes of the pancreas
Relate the hepatic portal vessel with the "microsomal fraction"
(smooth endoplasmic reticulum of the hepatocyte).
This gives the liver a chance to detoxify what is absorbed from the gut before
it gets to the systemic circulation
"A lesion in the lateral hypothalamus (LH) gives you a thin rat, hence the
LH is a hunger center." What have we learned since this conclusion was
first reached that gives us a different view of the role of the LH?
The LH has the dopamine tract that is useful in motivation (affect) in general
this page was last revised 7/13/09
**The hormone lecture
Hormones
Fox Chapter 11, part of chapters 2, 9, 19,
20
Introduction
Metazoans (animals with more cells than protozoans) require systems of
integration
INTEGRATION: Hormones, paracrine (local) & nervous system
"endocrine" - ductless, into blood stream
vs. exocrine (like digestive - saliva etc.)
Three steps:
cells with blood vessels for release
hormone transported in the circulation
target cell with receptor
Two mechanisms
(1) receptor molecule on membrane
(2) enter cell and bind receptor
Overview
TRANSPARENCY (From intro bio)
Fig. 11.1
I. Traditionally, this material starts with a picture of the major glands
II. Then it covers Pituitary three ways
(1) posterior pituitary
(2) anterior pituitary as "master gland" (and the other glands it
controls)
(3) anterior pituitary (affects not mediated through other glands)
III. Then it covers other glands (not controlled by the pituitary)
IV. I will then give you a dose of "signal transduction" concentrating
on steroids, thyroid and retinoic acid.
V. I will cover sex hormones in detail last (after glossing over them under
II.(3) [above])
A later lecture outline, Reproduction, will take off beyond III. and V.
Posterior pituitary
Fig. 11.13
(related to kidney coverage)
neurosecretion from hypothalamus (peptides)
"suprachiasmatic" means over the optic chiasm
"paraventricular" means near the (third) ventricle
oxytocin (milk, delivery)
(synthetic to induce labor)
Covered in Excretion lecture: ADH action on kidney
vasopressin (ADH), H2O and blood pressure
alcohol, caffein inhibit anti [diuresis] hormone
Anterior pituitary
Fig. 11.15
Median eminence from hypothalamus to pituitary
Secretion of releasing (and inhibiting) hormones (peptides) at pituitary stalk
Portal system
Anterior pituitary and its hormones (peptides)
Fig. 11.14
(on right of figure) Master gland to show glands controlled by pituitary
(thyroid, adrenals, ovary, testes) Trophic (tropins like
"gonadotropins")
(on left of figure) not using other endocrine glands (Growth hormone and
Prolactin)
Non-trophic hormones
(not where pituitary acts as master gland to control other glands)
GH - 200 a.a. -bone, muscle, not fat, -> liver to make somatomedins
GH - gigantism (bones grow long if too much GH when young), dwarfism (if too
little GH when young), acromegaly (bones grow too thick if too much GH when
already grown up, danger of GH abuse), abuse by body builders, dangers of
extracts,, now available through recombinant DNA research
Prolactin - milk production, like GH (same ancestral gene)
Trophic hormones
(like gonadotropins) "Master Gland"
sex hormones from pituitary (more details later):
LH (female) = ICSH (male); (luteinizing) (interstitial cell)
FSH (follicle)
non-sex trophic hormones from pituitary:
TSH (thyroid)
ACTH (adrenal cortex)
TRANSPARENCY (From intro book)
Review - same material, intro course
Thyroid hormones
(recall that thyroid was used as hormone example in first lecture outline)
Influence on metabolism, but not as obviously as epinephrine, insulin, glucagon
or even glucocorticoids.
Fig. 11.25
Negative feedback with pituitary
Hypothalamus -TRF-> + Ant. Pituit. -TSH->+ Thyroid -> thyroxine-
- neck thyroxin (T4), triiodothyroxine (T3) iodine, sea food (and iodized salt)
Fig. 11.3 (also shown in an earlier lecture)
T3 and T4
TRANSPARENCY (Figs 11.24, 11.26)
Goiter (thyroid overgrows if too little iodine in diet)
Cretinism if too little in infant, hypothyroid, hyperthyroid
Change in salmon during salt to fresh water change, metamorphosis in frog
Problem of radioactive iodine (like from reactor leaks) - helps to take large
doses of non-radioactive iodine to compete
Adrenal gland
Fig. 11.20
Adrenal cortex - Glucocorticoids stimulate metabolism, inhibits inflamation.
JFKennedy had too little glucocorticoids (needed replacement therapy) which
would create a situation of no feedback Addison's - too
much ACTH (darkens skin like MSH).
pro-opiomelanocortin - big peptide cleaved to ACTH, MSH, endorphins,
enkephalins
Emphasize regulation, negative feedback
Fig. 11.18
Zona glomerulosa - mineralocorticoids
Zona fasciculata and reticularis - glucocorticoids and androgens
Mineralocorticoids, the best known being Aldosterone helps kidney retain salt
Adrenalectomy causes salt loss and salt appetite.
Sweat glands are not as efficient at retaining salt as kidney.
That is why "Gatorade" (electrolyte) is used by athletes.
Salt is also lost in cystic fibrosis (mutation of CFTR (cystic fibrosis
transmembrane conductance regulator)
Female reproductive cycle
good example of Regulation, Negative feedback
CHAULKBOARD DIAGRAM
Hypothalamus - RF's (peptides)
(chaulkboard diagram is also here, peptides in
black, steroids in red)
Pituitary makes peptide hormones "gonado-trophic hormones"
(gonadotropins, FSH and LH)
gonads (ovaries) make steroid hormones (estrogen and progesterone)
Feedback system plus effects on endometrium (lining of uterus)
FSH (follicle stimulating hormone) stimulates estrogen release from follicle
estrogen inhibits FSH
estrogen turns on LH (lutenizing hormone) release
estrogen begins buildup of endometrium
surge of LH causes ovulation
then follicle becomes corpus luteum that puts out progesterone
progesterone inhibits LH and FSH
progesterone also stimulates buildup of endometrium
to finish cycle, low FSH & LH which lets estrogen and progesterone go down
(corpus luteum starts to go away)
with low estrogen and progesterone, endometrium breaks down (menstruation)
with low estrogen and progesterone, pituitary is not inhibited so FSH starts
(if pregnant, HCG [human corionic gonadotropin] maintains corpus luteum
progesterone (from maintained corpus luteum) maintains endometrium
Here is a primary
follicle, a growing
follicle, the mature
follicle, and the corpus luteum from
our histology course.
Human corionic gonadotropin
Menstruation in primates
Estrus cycle - dogs heat 2x/yr, cats 3x/yr
Rabbits reflex ovulators
Pill Progesterone and Estrogen inhibit ovulation
28 day pill 7 duds: 1st 4 days, last 3
"combination pill"
Weight gain, circulation problems
lower proportion of estrogen
Rhythm - sperm viable 48 hr, ovum 15 hr: 3-4 day abstinance
The male pattern
FSH for spermatogenesis
LH (ICSH) to stimulate interstitial cells to release testosterone
Glands not controlled by pituitary
Adrenal medulla
Fig. 9.8
while on the topic of the adrenal gland,
Adrenal medulla (vs cortex under pituitary control)- Epinephrine, (alias
adrenalin) - activates body
Autonomic (vs voluntary) motor control: sympathetic (vs parasympathetic)
Sympathetic nervous system uses norepinephrine at postganglionic synapses.
Sympathetic - "fight or flight"
Helps in metabolism to release glucose to blood stream
Muscles activity up, peripheral circulation and digestion inhibited
Heart rate goes up
Glucose (insulin and Glucagon) and diabetes
was moved from here to earlier
Calcium homeostasis
TRANSPARENCY (From introductory book)
Thyroid 2 glands (pituit - thyroxine TSH) vs:
Thyroid - thyrocalcitonin - blood Ca2+ down
Parathyroid - parathormone - blood Ca2+ up (from bones)
near thyroid gland in neck
Vitamin D sunlight, rickets, fish oil, hormone, absorption from gut
Osteoporosis - bone deterioration with age especially in women
Ca2+ very important, muscle (later), nerve (later)
Fig. 11.28
review, parathyroid hormone
Fig. 19.18b
PTH increases blood Ca2+
Osteoclast uses enzymes and acid to dissolve bone CaPO4
When calcium is needed a lot, bone depleted.
Osteoporosis, more common in women because of Ca2+ use in lactation.
Fig. 19.22
PTH effect on bone shown again here plus:
In kidneys, Ca2+ reabsorption is increased
and
In kidneys, 1,25-Dihydroxyvitamin D3 is made
(and that, in turn, increases intestinal absorption)
Working the vitamin D topic backward:
Fig. 19.21
kidney enzyme (1-alpha-hydroxylase) acts on 25-hyrdoxyvitamin D (from liver)
and
Fig. 19.20
Vitamin D from sunlight in skin
(plus liver and kidney shown in this figure)
Fig. 19.23
Calcitonin from the thyroid does the opposite
Steroids, etc
Fig. 2.23
structures of steroids
Structures of cholesterol, cortisol, testosterone, estradiol
Fig. 11.2
reactions of steroids
shows structures and locations of secretion
Interestingly, Cholesterol -> -> Progersteone (corpus luteum) ->
->Testosterone (Leydig cells) -> estradiol (follicles).
Fig. 11.5
steroid hormone receptor is protein that dimerizes
each receptor binds an HRE (hormone response element) (DNA sequence)
mechanism of hormone action is to activate gene transcription (into mRNA)
Estrogen
Menopause (pause in the menes) ["change of life" at about 50] - lack
of estrogen.
(Some hysterectomy or ovarian cancer surgeries might also deplete because of
ovarectomy).
Many symptoms, hot flashes most obvious short term effect.
Osteoporosis most obvious long term effect.
For me, this site worked with explorer, not netscape - estrogen
(hormone) replacement therapy
Hotly contested (a lot of negative press lately), partly because estrogen
increases chances of breast cancer.
There is a drug, Tamoxifen
that blocks estrogen's effects, differently in different tissues.
Recent literature
J.L.Turgeon, D.P.McDonnell, K.A.Martin & P.M.Wise, Hormone therapy:
Physiological complexity belies theraputic strategy, Science 304, 1269-1273,
2004
Estrogen and progesterone receptors in cardiovascular, neural, immune,
gastrointestinal and musculoskeletal systems.
Menopause (average age 51) vasomotor flashes, vaginal dryness, urinary
symptoms, osteoporosis, CHD (coronary heart disease.
Hence chronic estrogen therapy (ET) for CHD and osteoporosis.
A well intentioned study, WHI (women's health initiative) tested placebo,
estrogen & estrogen-progestin.
Discontinued because of increase in breasst cancer, CHD, stroke and venous
thromboembolism (but they did decrease fractures and colon cancer)
Human ovary: 17beta-estradiol.(E2) AND estrone (E1)
Study used conjugated equine estrogen (CEE) extracted from pregnant horse
urine, many estrogens including sulfated estrogens.
Why this matters is that there are several types of estrogen receptors
differentially activated by different estrogens.
Study used continuous oral administration, and hormone through hepatic portal
system highly activates estrogen receptors in the liver, changing important
proteins like angiotensin precursor.
Transdermal patch would be very different.
Women is study were fatter than usual.
Human progesterone vs study's medoxyprogersteone acetate (MPA), again affecting
different receptors differently, also MPA activates glucocorticoid receptor.
There are several estrogen receptors, alpha and beta. and many ways they
influence transcription.
"Antiestrogen" tamoxifen is antagonist in breast but agonist in bone
and uterus, so now called SERM (selective estrogen receptor modulator).
Better SERMs are being found.
Androgens
Anabolic steroids - muscle growth, bone growth, increased hemoglobin
There is an androgen from the adrenal - DHEA dehydroepiandrosterone
Increased secretion of testosterone at puberty has many obvious effects
including on larynx
Absence of androgens by castration decreases seminal vesicle and prostate
The whitish structure in this figure is the seminal vesicle
In this figure, the seminal vesicle of castrated and normal
mice are compared
Fig. 20.14
Interestingly, many of testosterone's effects are mediated by estradiol-17beta,
made by aromatase (in a process called "aromatization," note aromatic
[in the organic chemistry sense] ring).
DHT (and several subsequent metabolites) made by 5alpha-reductase
Fig. 20.7
This step takes place in cells
When I typed "five alpha reductase" or the like into my search
engine, I got hits on hair loss, concerning male pattern hair loss
(androgenetic alopecia) accelerated by DHT and alleviated by a drug, Propecia
Some wierd disorders
5alpha-reductase
deficiency -> "testes-at-twelve" (at puberty, testes descend,
clitoris becomes penis etc when there is enough testosterone to overcome
deficit) There is a pedigree in the
Dominican republic
androgen receptor mutation (androgen insensitivity syndrome [AIS]) ->
testicular feminization, children think they are females until there is no
menstruation
There are androgens from adrenal, so with Congenital adrenal hyperplasia, CAH,
clitoris is large and behavior is "tomboy"
Signal transduction
TRANSPARENCY (From introductory book)
"gene"
sequence coding for protein (mRNA) is copied from exons with introns spliced
out
"upstream" of gene, proteins binding promoter and enhancer regulate
transcription
Fig. 11.4
steroid hormone
Carrier protein, receptor, DNA
Fig. 11.6
thyroid hormone
Carrier protein-T4, receptor-T3, DNA
Fig. 11.7
thyroid hormone
involves retinoic acid
Fig. 11.8
Remember signal transduction for G protein coupled receptor
TRANSPARENCY (From introductory book)
integrates the above point with epinephrine evolution of glucose
Prostaglandins, etc
Fig. 11.33
prostaglandins (mediators of inflammation) are derived from fatty acid
(arachidonic acid, 20:4) using cyclooxygenase (COX)
Prostaglandins have different actions in different places; take platelet
aggregation -- TXA2 stimulates clumping, PGI2 prevents them from sticking to
walls of vessels; it is the TXA2 aspect that is why you take aspirin to prevent
heart attack and should not take aspirin before surgery (etc.).
leukotrienes (mediators of inflammation) ... use lipoxygenase
NSAIDS (non-steroidal anti-inflammtory drugs) aspirin, ibuprofen, inhibit
prostaglandin synthesis by inhibiting cyclooxygenase (COX-1 & 2)
nonspecifically, problems in stomach
Celebrex, Vioxx, Bextra inhibit prostaglandin synthesis by inhibiting
cyclooxygenase (COX-2); popular for arthritus, but Merck pulled Vioxx 10/04 for
increasing cardiovascular problems, and later Bextra was pulled.
Aspirin is anti-inflammatory, anallgesic, antipyretic, anticoagulant,
implicated in Reye's
syndrome.
The Biology department's primary expert on endocrinology is Dr. Asa who is director of research at
the St. Louis Zoo. As an adjunct Professor in SLU's Biology department, she
teaches the popular course, "Introductory Endocrinology" BL A450-01
Exam questions from 2004 - 2008 relevant to this outline
Loss of what hormone would cause an adrenalectomized animal to crave salt?
aldosterone
What is the name of the disorder of too much growth hormone as an adult?
acromegaly
Vitamin D helps to keep the blood levels of what substance correct?
Ca2+
On what kind of molecule would you find a sequence known as a "hormone
response element (HRE)?"
DNA
Historically, shortage of what mineral caused some inland people to develop
goiter?
iodine
Why are alcoholic beverages contraindicated to stay hydrated in times of heat
stress? (Make sure your answer says what happens to the relevant hormone
level.)
alcohol inhibits ADH, more water is lost through kidney
Non-steroidal antiinflammatory drugs (NSAIDs) block converrsion of what fatty
acid to prostaglandins?
arachidonic
After ovulation, the estrogen secreting follicle turns into a tissue that
secretes what hormone?
progesterone
In the process where epinephrine causes glucose release from liver, what enzyme
does cAMP activate?
protein kinase A
What kind of chemical is a gonadotropin?
peptide
The birth control pill feeds back to inhibit what pituitary peptide (to prevent
maturation of the follicle)?
FSH
What does the osteoclast do to assist in Ca2+ homeostasis?
cause bone to release Ca2+
A receptor (protein) for T3 makes a heterodimer with a receptor for what
substance?
retinoic acid
Hyperplasia of what gland would androgenize a female?
adrenal
What pituitary hormone maintains the cells that secrete testosterone?
LH
What syndrome results from 5a-reductase deficiency?
testes at twelve
What treatment has been standard for relief of hot flashes?
estrogen replacement therapy
Name one molecule in the biosynthetic pathway between cholesterol and
testosterone.
progesterone
Within the ovary, what tissue produces estrogen?
follicle
Why is the term "anabolic" applied to some hormones?
growth (muscles, bone, hemoglobin)
Where are the cell bodies of the cells whose axon terminals release ADH and
oxytocin?
hypothalamus
To mediate many of the effects of testosterone, aromatase converts it to what?
estradiol
After the alpha subunit of the heterotrimeric G protein binds GTP, what does it
do to GTP?
breaks it to GDP (and P)
What close relative of retinal (retinene, the part of rhodopsin that absorbs light)
is important in the activation of the hormone response element by
triiodothyroxine?
retinoic acid
ACTH triggers the release of what hormone from its target gland?
cortisol
What is the tissue responsible for producing the gonadotropin that supports the
corpus luteum early in pregnancy?
chorion
Why is such a small amount of thyrotropin-releasing hormone TRH needed?
because portal system delivers straight to anterior pituitary
Although dopamine is a transmitter itself, it can be converted into what other
neurotransmitter by the enzyme dopamine beta-hydroxylase?
norepinephrine
What hormone would put calcium back into bones?
calcitonin
A surge of what peptide leads to ovulation?
LH
What second messenger activates protein kinase when the beta-adrenergic
receptor of a liver cell binds epinephrine?
cAMP
Increased testosterone at puberty affect what organ to turn sopranos into
altos?
larynx
What would happen to the TSH level if dietary iodine were deficient?
go up since negative feedback from thyroxine is decreased
What cleavage product of pro-opiomelanocortin would be high in Addison's
disease?
ACTH
How would calcitonin regulate Ca2+ at the level of the kidney?
decrease resorption
In the term "gonadotropin," what does the suffix "tropin" refer
to?
has trophic effect
What would happen instead of increase in bone length if growth hormone were too
high in the adult?
bones would get thicker
In the old days, what would cod liver oil be used for?
vitamin D (and A) replacement
In the pathway 7-dehydrocholesterol -> vitamin D3 -> 25-hydroxyvitamin D3
->1,25-dihydroxyvitamin D3, where does the first conversion take place?
in the skin
Osteoclasts contribute to the breakdown of CaPO4 plus what additional
component, a protein, in bone?
collagen
A surge of LH mediates ovulation plus the conversion of the follicle into what
tissue?
corpus luteum
What is it called when, because of low progesterone, the endometrium is no
longer supported?
menstruation
What hormone supports the endometrium during pregnancy?
progesterone
What effect does calcitonin have on the kidney?
Allows for CaPO4 loss in urine
Testosterone is converted to dihydrotestosterone (DHT) by what enzyme?
5-alpha-reductase
Tamoxifen used to be called an antiestrogen but might now be better referred to
as a SERM (selective estrogen receptor modulator). Why?
antagonist in some tissues but agonist in others
A heterodimer of receptors for thyroid hormone and retinoic acid (together with
their respective ligands, thyroid hormone and retinoic acid) binds to what
specific location on what molecule?
response element on DNA
Estradiol-17b is made by aromatase from what steroid (the immediate precursor)?
testosterone
Give a reason why the exact same mixture of hormones might have different
effects in a woman if given orally vs via a transdermal patch.
would go to liver by hepatic portal vessel if taken by mouth
A steroid hormone receptor is famous for binding the hormone as well as what
major macromolecule?
DNA
Give the name of a class of molecules produced by enzymes acting on arachidonic
acid (20:4).
prostaglandins (leukotrienes)
What type of chemical is the product of the Leydig (interstitial) cells?
steroid
In terms of how they inhibit prostaglandin synthesis, how would a COX2
inhibitor differ from traditional NSAIDS like aspirin?
aspirin was non-specific (COX1 & 2)
Chemically, what type of molecule is a gonadotropin?
peptide
Where is the receptor for steroid hormones?
inside the cell
What would be the most common reason to administer oxytocin (or a synthetic
version of this hormone)?
induce labor
Why would very small amounts of TRH be needed for adequate homeostatic control?
portal vessel from hypothalamus to pituitary means that it is not diluted by
the systemic circulation
Although steroids in the birth control pill would have a trophic effect,
building up the endometrium, they block pregnancy. By what mechanism?
by inhibiting FSH and LH, they prevent ovulation
What is the effect of the hormone of the adrenal medulla on heart rate?
adrenalin increases heart rate, of course
A lot of hormone from the parathyroid gland would decrease calcium in what
notable reservoir in the body?
bone
Ovulation, as well as the conversion of the follicle to the corpus luteum, is induced
by a surge in what pituitary peptide?
LH
PTH, the hormone of the parathyroid, acts on the kidney to stimulate Ca2+
reabsorption and inhibit PO4- reabsorption. What other effect does PTH have on
kidney to help to increase plasma Ca2+?
formation of 1,25-dihydroxyvitamin D3 (increase 1alpha-hydroxylase activity
What famous steroid hormone is an intermediate in the conversion of
progesterone to estradiol-17beta?
testosterone (also androstenedione)
A DNA-binding domain is a hallmark of what kind of molecule that binds to a
hormone response element?
steroid hormone receptor protein
Testosterone is converted by 5alpha-reductase or by aromatase into (name one of
these steroids)?
dihydrotestosterone, estradiol-17beta
How does cAMP activate the kinase?
binds to and removes inhibitory subunit from catalytic subunit
Answer one of the following for the precursor that cyclooxygenase turns to
prostaglandins and lipoxygenase turns into leukotrienes - (1) name it, or (2)
say what kind of molecule it is, or (3) where does it come from?
arachidonic acid ((20:4), fatty acid, from membrane phospholipid
Who would suffer from acromegaly?
adults with too much growth hormone
Why would your skin be dark if you had Addison's disease (inadequate cortisol,
no feedback, too much ACTH)?
ACTH mimics melanocyte stimulating hormone
Chemically, what type of hormones are the hormones of the adrenal cortex?
steroids
If estrogen and progesterone maintain the endometrium, how come women taking
the birth control pill still have menstruation?
estrogen and progesterone are not given for a few days
Why would hyperplasia of the adrenal masculinize a female?
adrenal cortex makes anabolic steroids like testosterone, too much if there is
hyperplasia
Why is the area upstream of a gene's coding sequence relevant to the actions of
retinoic acid, thyroxine and steroid hormones?
this area is the promoter where steroid hormone receptors , retinoic acid
receptors, etc bind
The G protein coupled receptor signals to the next molecule in the cascade,
namely the G protein. Why is it called a G protein?
binds GTP
Why is the term "neurosecretion" used for some hormones and give one
example.
neurons with axons release chemicals from their terminals near blood vessels,
ADH, oxytocin, releasing hormones
What happens if there is too much growth hormone in the fully-grown adult?
bones grow in thickness, not length, acromegaly
What leads to hypertrophy of the thyroid gland (goiter)?
deficiency of iodine
Why do they need to build fish ladders beside tall dams?
salmon go up their native stream to spawn
What type of chemical is the hormone secreted by the follicle?
steroid
After implantation, what peptide stimulates the corpus luteum to continue
progesterone secretion?
human chorionic gonadotropin
What important cell, other than the hormone-secreting cells, is present in the
follicle?
the egg
What type of chemical is the hormone that has a trophic effect, causing the
Leydig cells (interstitial cells) to release their hormone?
peptide
H2CO3 is split in osteoclasts. Where do the two portions go and why?
H+ for acidity into bone on one side of the osteoclast, HCO3- exchange with Cl-
on the other side to start Cl- toward the bone to make HCl
Which hormone from a gland inside the neck has the same effect on plasma
calcium ion concentration as 1,25-dihydroxyvitaminD3?
PTH
Describe why the system of the hepatic portal vessel might be relevant in
estrogen replacement therapy.
Any chemicals, if taken orally, might be converted to other things by the liver
Testosterone gets converted to other steroids for its activity. Tell me one of
the enzymes that effects these conversions.
5-alpha reductase (to 5 alpha DHT) or aromatase (to estradiol-17beta
One part of the retinoid X receptor (RXR) binds 9-cis retinoic acid. What does
the other part of this molecule bind?
DNA (the RARE)
Why doesn't the alpha subunit of the heterotrimeric G protein activate the
adenylate cyclase indefinitely?
it has GTPase activity (etc.)
Why would a selective estrogen receptor modulator (SERM) be so potentially
useful for bone health?
have the beneficial effect on osteoblasts but not promote breast cancer or
cardiovascular problems
Why might you want to inhibit the normal function of osteoclasts?
to stave off osteoporosis
Many hormone receptors are on the cell membrane. How can steroid hormone
receptors work when they are inside the cell?
by binding steroid hormones and also binding DNA at hormone response element
ACTH is cleaved from what peptide precursor?
proopiomelanocortin
What organ are the steroid-secreting zona fasciculate and zona reticularis part
of?
adrenal cortex
Out of a long laundry list, tell me one precursor of the hormone from the
adrenal medulla.
tyrosine, l-DOPA, dopamine, norepnephrine
Tell me one of several molecules that are precursors for all of these:
hydrocortisone, testosterone, and estradiol-17beta.
cholesterol, pregnenolone, progesterone
"A gene is the coding sequence for a protein." The truth but not the
whole truth. Relative to this, where is the hormone response element?
upstream of the coding sequence
What is the precursor of leukotrienes, and where (in the cell's anatomy) does
it come from?
arachidonic acid, in membrane lipid
Why did COX-2 inhibitors show so much promise, and why were some pulled from
the market?
reliece arthritic inflammation without interfering with gastric mucosa,
increased chance of heart attack
By what mechanism is estrogen good for bones?
it promotes osteoblasts
What is it called when a hypothyroid condition as an infant leads to deficient
neural development?
cretinism
What is the condition where there is too much ACTH? - Answer one: (1) name of
condition (2) What is there too little of? Or (3) Why does the skin get dark?
Addison's disease, too little cortisol, ACTH is like MSH (melanocyte
stimulating hormone)
The adrenal cortex is famous for producing androgens, glucocorticoids and (what
else?).
mineralocorticoids (aldosterone)
Norepinephrine is converted to epinephrine to be the major hormone of what
(specific) gland.
Adrenal medulla
Why would cod liver oil be a useful dietary supplement for some people?
Vitamin D
Why was there the conventional wisdom that estrogen by patch was safer than
oral administration?
Swallowed, the liver could make many other products
Why was the women's health initiative study discontinued?
Increase in breast cancer, coronary heart disease
For "androgenic alopecia" tell me either (1) what these words mean,
or (2) what an enzyme or the hormonal product it catalyses has to do with that.
Male pattern baldness, 5 alpha reductase makes DHT
Address the terms "paraventricular" and "supraoptic" in ONE
of the following ways: (1) What part of the brain are they in? (2) How did
those nuclei get those names? (3) What structure is the output of this
neurosecretion? Or (4) What are the hormones?
hypothalamus, around the (third) ventricle and above the optic chiasm,
posterior pituitary, ADH or oxytocin
For one portal system, the first capillary bed is in the pituitary stalk.
Answer ONE of these (1) Where are the cell bodies responsible for secretion
into this vascular bed? Or (2) Where (specifically) is the second capillary
bed?
hypothalamus, anterior pituitary
Distinguish between what happens with too much growth hormone as a child vs as
an adult.
become a giant, acromegaly
How come women who took the birth control pill still menstruated?
out of the 28 days, the steroids are not in the last 5 days so the endometrium
is not supported
What are the two different functions of the pituitary gonadotropins in the
male?
FSH spermatogenesis, LH getting the interstitial cells of Leydig to secrete
testosterone
A surge in LH converts the follicle to the corpus luteum and (what else does it
achieve?).
causes ovulation
Why doesn't the endometrium break down once FSH and LH stop maintaining the
corpus luteum when implantation has occurred?
HCG supports the corpus luteum, so there is still progesterone
Starting with 7-Dehydrocholesterol, what is the order of action of the 3 separate
ORGANS in the production of the active form of vitamin D?
skin, liver, kidney
A hormone from the thyroid has (what effect on the kidney?) for calcium
homeostasis.
calcitonin stimulates excretion of Ca2+
Progesterone is the precursor of what two sex steroids?
testosterone and estradiol
Where, specifically, is the hormone response element?
on the DNA upstream of the coding sequence for the protein
Why would a mutation in the receptor that caused insensitivity to androgens
have the effect it has in androgen insensitivity syndrome?
testicular feminization b/c there is no response to hormones like testosterone
Why at the time, was the availability of new COX-2 inhibitors heralded as such
an important development?
arthritis symptoms taken care of without the COX-1 interference with the
gastric mucosa
The thyroid receptor makes a heterodimer with a receptor for what signaling
molecule?
retinoic acid
this page was last revised 7/21/09
** The reproduction lecture
Animal Reproduction and development
From speech of Aristophanes:
...The sexes were not as they are now...the primeval man...had four hands and
four feet, one head with two faces...Terrible was their might and
strength...and they made an attack upon the gods...Zeus...said: "Methinks
I have a plan which will humble their pride and improve their manners; men will
continue to exist, but I will cut them in two...After the division of the two
parts of man, each desiring his other half, came together, and throwing their
arms about one another, entwined in mutual embraces, longing to grow into
one...
-Plato Symposium
Love (sweet Chloe) is a god, a young Youth, and very fair, and wing'd to
flye... His power's so vaste, that that of Jove is not so great... For there is
no med'cine for Love, neither meat, nor drink, nor any Charm, but only Kissing,
and Embracing, and lying naked together.
-Daphnis & Chloe By Longus Translated out of Greek by George Thornley Anno.
1657
Fox Chapter 20
MALE
Meiosis and sperm
Fig. 20.16
Spermatogonia (mitosis and meiosis) - primary spermatocytes
- meiosis (both divisions) - spermatids (scrotum cooler)
Sperm (meioses throughout adult life) Seminiferous tubules
300 million/ ejaculation
Fig. 20.13
Testes - seminiferous tubules make sperm, stimulated by FSH, inhibin for
feedback
Interstitial (Leydig) cells produce testosterone, stimulated by LH (ICSH),
feedback
Fig. 20.12
Low mag section of testis, higher mag showing seminiferous tubule and
interstitial cells
Testes in short day
hamsters are smaller than in long day hamsters
Fig. 20.17
An even higher magnification showing Sertoli cell that supports spermiogenesis,
has histology
(histology picture)
Semen
Fig. 20.20
male anatomy
Semen:
Bulbourethral (Cowper's) gland (early overflow from sexual excitement)
Seminal vesicle - fructose, amino acids, mucus, prostaglandins (uterine
contractions)
Prostate - alkaline (infection, cancer most men > 50)
Capacitation of sperm
Epididymis
Vas deferens - peristalsis -(vasectomy 100% effective- permanent long term
effects unknown)
Urethra (of course, it is output here for which condom is a form of
contraception)
The prostate story.
Cancer in men >50, diagnosed by paplation
PSA=prostate specific antigen, 1 is low, 5 is high, but not specific to cancer,
might be high after having sex
Several "remedies" including selenium
Surgery and radiation, etc.
Slowly developing cancer
Complications - incontinence (for #1, even #2), possibly impotence (ED)
For ED, Viagra, Levitra, Cialis
Fertilization
Many sperm attack one egg, only one fertilizes - fast (electrical) response prevents
others
20.39
acrosome, nucleus, mitochondria (not go into egg), flagellum
Review:
Parasympathetic arterioles (unique, usu only symp.) - erection (sleep)
ACh - NO - smooth muscle dilate- viagra blocks breakdown enzyme
NO synthase in cavernous artery and corpus cavernosum
Robert F. Furchgott, Louis J. Ignarro, Ferid Murad Nobel 1998
"for their discoveries concerning nitric oxide as a signalling molecule in
the cardiovascular system"
Sympathetic - ejaculation inhib erection
Fig. 20.21
Here is a picture
from our histology course
showing the spongy tissue of the corpus cavernosum which becomes engorged with
blood to mediate erection.
rodents racoons walruses - bone
Sympathetic - ejaculation inhib erection
FEMALE
Review
Fig. 20.34
Here is the typical text book diagram depicting the menstrual (ovarian) cycle
(covered earlier)
For convenience, I used the term "eggs" earlier, now I get more
official
Meiosis, ovary, steroids
Fig. 20.32
I showed this to you before
primary oocyte in early follicle
secondary oocyte in mature follicle
Fig. 20.31
Here's how that relates to meiosis
Primary oocyte (2-4 million at birth, 1st meiotic prophase)
(400,000 at puberty, only 400 used)
(no oogonia after 3 mo)
Secondary oocyte + polar body
(Graffian follicle finish 1st meiosis) ovulation
if 2 ovulations - DZT - 2 amnions, 2 chorions
twins 1.2% of births, of these 70% "fraternal"
DZT run in family
Uterus, fertilization, and early development
Fig. 20.24
Review
I showed this to you before
anatomy of ovary, and relation of ovulation to fimbriae of uterine (Fallopian)
tubule
Tubal ligation (laparoscopy) 100% effective. Reverse?
Cervix (diaphragm, cervical caps, foam, spermicidal jelly)
Fig. 20.42
Fallopian tube (fimbria capture ovulated egg - Sperm meets, 2nd meiosis makes
ootid 3 polar bodies discarded nucleii
Division in Fallopian tubes
Blastocyst (trophoblast, blastocoel, inner cell mass)
(trophoblast - >chorion -> placenta)
(inner cell mass -> embryo -> fetus)
IUD prevent implantation, irritate, after previous child, not for everybody
legal question
if inner cell mass divides, Monozygotic (identical) twins MZT (2 amnions, 1
chorion), 30% of twins
Fig. 20.44
Shows trophoblast, implantation and a little development
While I have this up, I will talk about "stem cell research"
This relates to cloning.
Cloning
(Not cloning as in cloning a gene, but cloning an organism)
1950's work on amphibians - Since all nuclei should have all the genes, any
nucleus should work to make whole organism, taken out of, for instance, an
intestine cell. But not all cells work, so put the nucleus into an egg where it
is certain that the nucleus already there has been destroyed.
work to make sheep Dolly. Nuclear transfer by removal of egg nucleus followed
by fusion with cell with diploid nucleus. Need to implant into a surogate mother.
Cloning has been extremely controversial, and human "reproductive
cloning" is banned. Some scientists hoping to advance medical treatments
would like to distinguish "theraputic cloning" from cloning to
produce a person genetically identical with the donor. Some think the issue
would be simplified by use of the term "nuclear transplantation."
Stem cell research
Because cells lose their pluripotency, researchers have focussed on their
discovery that embryonic stem cells are better at differentiating into cells
that can repair cell damaged areas such as in the case of spinal cord injury;
the issue is very controversial because it may encourage practitioners to
create and destroy human embryos for no other purpose than to harvest stem
cells. Of note, there may be "left-overs" (it is hard to find a
diplomatic euphemism) from in vitro fertilization after a couple has had all
the children they want (that might go to "waste"). For this reason,
for humans, only the use of some 60 cell lines that are already in culture was
dictated in the US by President Bush.
Several colleagues and I are collaborating
to cure blindness in a mouse mutant with cells that started as embryonic and
were induced to become precursors of nerve cells; identified by green
fluorescent protein, here is
a cell that has been put into the retina and is beginning to show a neuron-like
phenotype.
Cursory overview of development
Fig. 20.46
trophoblast implants becomes chorion -
Chorionic villus biopsy - early genetic testing
Amniocentesis-later genetic screening
placenta - exchange, diseases like rubella, alcohol, drugs
Fig. 20.45
make HCG 2 wks - 4 mo (pregnancy test)
to maintain corpus luteum
Fig. 20.5
(not graphic)
2 sexes from 1 primordium
H-Y antigen = testes differentiating factor
then testosterone alters development
MIF (Mullerian inhibiting factor) contributes to development of male
"plumbing" female pattern is the default pathway, clitoris is
equivalent of penis
Prof Aldridge teaches several
courses and does research on reproduction. Prof Ogilvie teaches developmental biology.
Prof. Schreiweis teaches
embryology.
Exam questions from 2004 - 2008 relating to this outline
How many oogonia does a woman have at puberty?
none
A ball consisting of trophoblast plus what other clump of cells becomes
implanted in the endometrium?
inner cell mass
When is meiosis completed in the "egg?"
when sperm meets egg
A low PSA reading is around 1 while a high PSA is 5. What does PSA stand for?
prostate specific antigen
Where is the acrosome?
tip of spermatozoan
Why might a physician want to test a sample of amnionic fluid?
to test prenatally for gene or chromosomal defects
Semen has components from seminiferous tubules, seminal vesicles, bulbourethral
(Cowper's) gland, and what other gland?
prostate
The trophoblast becomes the chorion, and the chorion, in turn, becomes what?
placenta
What divides to make monozygotic (identical) twins?
inner cell mass
Where does fertilization take place?
way up in uterine (Fallopian) tube
What becomes of the mitochondria of the spermatozoan during fertilization?
they do not go into the egg
Incontinence is a common consequence of what surgery?
prostate
What is the result of ligating and snipping the vas deferens?
man is no longer fertile
Where is the "egg" when meiosis is complete?
when the sperm fuses
What divides to make identical twins?
inner cell mass
Genetically, how are fully differented adult cells different from pluripotent
stem cells?
They both have the same genes, though only a limited subset are being expressed
in the former
One diploid primary oocyte undergoes two meitic divisions. How many cells that
can be fertilized result?
only one
What part of the blastocyst will eventually (much later) become the placenta?
trophoblast
How can a physician test for defects earlier than amniocentesis?
chorionic villus biopsy
What happens if neither MIF (Mullerian inhibition factor) nor testosterone are
present?
primordia of sex structures adopt female development
The PSA (prostate specific antigen) test is used to diagnose a predisposition
for what disorder?
prostate cancer
Why is development of uterus and clitoris considered the default pathway?
testes-determining factor (TDF), Mulleriasn-inhibiting factor and testosterone
actively cause indifferent gonad primordia to select the male pattern
Spermatogonia undergo meiosis to make sperm. In what way is this process
different for formation of oocytes in the adult human?
There come to be no oogonia in women, thus the entire meiosis does no occur
throughout life, way fewer gametes are formed, 4 sperm vs 1 oocyte and polar
bodies, sperm constant oocyte meiosis regulated when sperm meets egg
Name one of the glands that adds to sperm to make semen.
bulbourethral (Cowper's), seminal vesicle, prostate
Nitric oxide activates an enzyme that makes cGMP. (Maybe you did not know
this.) Why might some people take a drug to inhibit the enzyme that breaks down
cGMP?
for erectile dysfunction
Why is the IUD (intrauterine device) particularly controversial?
prevents implantation, not fertilization
Say where (or when) the second meiotic division occurs for the oocyte
uterine tubule, when sperm meets egg
What technique provides earlier information on genetic or chromosomal
abnormalities than amniocentesis?
chorionic villus biopsy
What specific body of cells divides to make monozygotic (identical) twins (and
also is a source of embryonic stem cells)?
inner cell mass
What is the "egg" called officially at the time of ovulation, and
what stage of meiosis or mitosis is it at at that time?
secondary oocyte, before meiosis II is complete
Tell me about oogonia in the human female between the first menstrual period
and menopause.
there are none
Why do proponents think that embryonic stem cells might be useful to treat
Parkinson's disease.
such cells are pleuripotent
An embryonic structure becomes the penis if testosterone is present. What does
it become without testosterone?
clitoris
Tell me about spermatogonia in the adult male.
diploid, replace themselves by mitoses, give rise to diploid primary
spermatocytes
Ligation and cutting of what tube is a common elective surgery for men to
achieve sterility?
vas deferens
Why might an elderly man decide not to have surgery after first being diagnosed
with prostate cancer?
it progresses slowly, surgery has side effects
Ovulation comes after a striking surge in what gonadotropin from where?
LH from anterior pituitary
Where (anatomically) does fertilization take place in the human.
in the uterine (fallopian) tube
How do dizygotic (fraternal) twins come about?
2 ovulations
Birth control prevents fertilization. Why is the intrauterine device
qualitatively different?
prevents implantation meaning that fertilization (and many cell divisions) have
already taken place
In cloning (Dolly, for example) what do you put into the surrogate mother and
where?
blastocyst to uterus
"Spermatogenesis: the formation of spermatozoa, including meiosis"
(from the glossary in your book). How is spermiogenesis distinguished from
spermatogenesis?
spermiogenesis is just the stripping of the cytoplasm of spermatids and the
streamlining of spermatozoa
For purposes of family planning, some men elect to have a straightforward
surgery that results in sterilization. What is done?
vasectomy = ligate and sever the vas deferens
Why might an elderly man decide not to have surgery for prostate cancer?
it is a slowly developing cancer, and possible side effects of impotence and
incontinence detract from the quality of life
As the sperm cell is about to fertilize the "egg," how far along in
its meiotic divisions is the egg?
arrested at metaphase II (i.e. meiosis I is complete, but not II)
When are primary oocytes formed from oogonia in the human female?
before birth
With the intrauterine device, which irritates the uterus, the likelihood of an
ectopic pregnancy is increased. How does ectopic differ from normal?
way up in uterine (fallopian) tube (instead of uterus)
What is the specific source of embryonic stem cells?
inner cell mass
What is the difference between identical vs fraternal twins in how they are
formed?
two ovulations both fertilized fraternal, inner cell mass divides identical
Why do researchers have high hopes for the use of embryonic stem cells for
eventual therapies for disorders like retinal degeneration and Parkinson's
disease?
they are pluriotent, amazingly form into needed cells if placed where they are
needed
Why should cells in the amniotic fluid give us information about genetic (and
chromosomal) abnormalities of the fetus (and not the mother)?
the amnion (and of course the fetus) are of zygotic (as opposed to maternal)
origin, so the fluid is surrounded only by cells from the fertilized egg
Under the influence of Mullerian inhibition factor (MIF) and (what else?) male
development is initiated instead of the female default pathway.
testosterone
How do the mitochondria in the sperm cell contribute to the DNA in the zygote?
They do not
Two meiotic divisions in the female result in only one "egg." What
did the other nuclei produced by meiosis become?
Polar bodies
In cloning Dolly, an egg was obtained, its nucleus was removed, a somatic cell
nucleus was put in, and cell divisions create an embryo (a hollow ball of
cells) in vitro. What did they have to do after that so that a
sheep was born?
Implant into a surrogate mother
Why would the intrauterine device (IUD) be considered to be particularly
controversial?
Well, even blocking fertilization might be controversial, but blocking
implantation is a really early abortion
Why does in vitro fertilization come up
in discussions of the benefits and controversities of stem cell research?
One possible source of embryonic stem cells would be "left overs"
once a couple has decided they have had enough children
this page was last revised 7/28/09
** Blood and the immune system outline
Blood and
antibodies
Fox Chapter 15 (immune system)
also part of Chap 13 (for blood)
A figure from Chapter 20
Fig. 13.1
Overview of blood cell types
plasma and hematocrit (formed elements), Buffy coat between
I. Plasma - (serum lacks fibrinogen) fluids, nutrients, O2, CO2, ions
proteins (synthesized in liver except gamma globulins)(clotting)
Albumins
Globulins
Fibrinogen
II. Hematocrit
Erythrocytes 5-6 million/ml
Leucocytes 5-10 thousand/ml
Platelets 250,000-400,000/ml formed from megacaryocytes
(antibodies) ions, wastes, hormones
Blood clotting
Fig. 13.9
Platelets 250,000/ml from megacaryocytes
Clotting Platelet adhesion then fibrin (from fibrinogen)
Cascades
activated Hageman factor
prothrombin -> thrombin
fibrinogen ->fibrin
Hemophelia is famous disorder
Hemophelia (4 SLIDES)
pedigree
Victoria, Nicholas II & Alexandra - Alexis, Rasputin
on X
problem with AIDS for clotting factor
Erythrocytes
Fig. 13.3
Red blood cells (corpuscles) (erythrocytes)
no nuclei
O2 transport, hemoglobin, anemia
last 120 days, made in marrow, recycled
iron recycling in liver is what makes feces dark (and skin yellow in jaundice
[hepatitis]) - bile pigments
Polymorphonuclear granulocytes
There are non-specific responses to injury
White blood cells (leucocytes as in leukemia)
Polymorphonuclear granulocytes (phagocytosis, etc)
neutrophil (60-70%) phagocytosis
here is a picture
from our histology course
of a neurtophil showing the complex nucleus
Fig. 15.2
chemotaxis after 30-60 min
more synthesized especially in bacterial infection
reset thermostat (pyrogens)
eosinophil (1.5%) phagocytosis
allergic and parasitic inflamation
basophil (0.1%) histamine containing
like mast cells
Phagocytosis and review slides
Fig. 15.1
Phagocytosis (cell eating), fusion of primary lysosome, formation of secondary
lysosome
SLIDES: blood cells (SEM= scanning electron micrograph))
white blood cell engulfing bacterium (Light Micrograph)
same (SEM)
SLIDES macrophage eating E. coli
macrophage - asbestos
fibrin (2 slides)
Monocytes
Fig. 15.6
Mononuclear cells
monocytes (5%) (as in mononucleosis) (phagocytosis)
late chemotaxis become macrophages
alveolar macrophages in lungs
Kupffer's cells in liver
Inflammation
Fig. 15.5
Inflammation and phagocytosis
Triad redness, warmth, swelling
Histamine (from mast cells, platelets)
lymphocytes:
There are specific responses involving antibodies and other mechanisms
T-cells (80%) (thymus - near heart) cell
(transplant) cytotoxic, suppressor, helper (AIDS)
B-cells (20%) (bone marrow, actually bursa of Fabricius) (become plasma cells)
antibodies
Blood groups
Fig. 13.5
Blood groups
This topic is fundamental and a bit confusing.
genotypes IA IA or IA i have phenotype A, A antigens, anti-B antibodies
genotypes IB IB or IB i have phenotype B, B antigens, anti-A antibodies
genotype IA IB has phenotype AB, A and B antigens, no antibodies
genotype ii has phenotype O, no antigens, antibodies to both A and B
O universal donor, AB universal recipient
There are already antibodies since blood group polysaccharides are like those
of bacteria even though there was no previous exposure to antigens. IgM not
cross placenta
Rh factor
- mother and + fetus problem if blood crosses over (during delivery)
problem is next time since IgG crosses placenta
treat mother with antibodies (passive immunity) then she will not mount active
immunity
Active and passive immunity
When I was a kid, nearly everrybody got measles, mumps, and chicken pox. We
were presumably immune for life (active immunity). When we had the disease was
part of out health record.
Vaccines - active immunity (like disease)
memory cells of immune system
Edward Jenner 1796 "encowment"
Farmers were less likely to get smallpox because they got a related disease,
cowpox
When I was a kid, you could not enroll in school without the scar
Smallpox is so completely eliminated that one issue is whether to get rid of
lab virus.
When I was a kid, there was (still) a polio epidemic.
A kid at a birthday party I went to got polio, so I went to the family doctor
for gamma globulin, passive immunity
(1954 Salk vaccine injected, soon Sabin vaccine in sugar cube)
Fig. 15.15
lymph system and nodes
Antibodies
Humoral immunity - B cells
Fig. 15.23
clones of plasma cells and memory cells derived from B cells for specific
antigens
Fig. 15.7
Another version of this figure
Fig. 13.4
(showing only erythrocytes)
Interesting continued development through life of monocytes, granulocytes and
lymphocytes from stem cells
note, the bone marrow which makes blood cells is mostly in the head and ribs,
the two most likely locations for X-rays which are dangerous
Fig. 15.8
Antigen (virus or bacterial coat, usually not self)
Antigenic determinant (epitope 5-15 anino acids)
IgD on B cells, antigen receptors
Fig. 15.10
Antibody
2 long chains and 2 short chains, variable region at the end of all 4 makes it
specific for antigen
An amazing mechanism where the gene is rearranged accounts for diversity.
IgG most abundant, monomer, cross placenta
Fig. 20.55
Antibodies cross placenta, also in mother's milk, and late weaning covers until
child's own antibodies are formed.
Fig. 15.26
IgE allergy, bind to mast cells (histamine)
T-cells
Fig. 15.17
helper T cells express CD4
antigen presenting macrophage
MHC major histocompatability complex 20 genes 50 alleles each
Class II MHC only on macrophages (and B lymphocytes)
antigen presented by to B cell
Fig. 15.18
cytotoxic (killer) T cells express CD8
Class I MHC - actually on lots of cells (including the infected cellsshown
here)
[try to match MHC (tissue typing) for transplantation]
Fig. 15.19
Interleukin-2 is released by helper T cells to cause killer and helper cells to
proliferate
Exam questions from 2004 - 2008 related to this lecture
What kind of cell becomes a macrophage?
monocyte
Presence of what in type O people would lead to agglutination if there were a
transfusion with any other type of blood?
anit-A and anti-B antibodies
Presence of what in type O people would lead to agglutination if there were a
transfusion with any other type of blood?
anit-A and anti-B antibodies
Eosinophils are a type of polymorphonuclear granulocyte. What is eosin?
a histological stain
What kind of molecule is IgG? (Be more specific than "protein.")
antibody
In a neutrophil or macrophage, after phagocytosis of a bacterium, what cellular
organelle full of enzymes fuses with the phagosome to destroy the bacterium?
lysosome
A B lymphocyte develops into what protein-producing cell?
plasma
When it is needed, what important protein does a plasma cell export?
antibody
What cell is specifically depleted in AIDS?
Helper T
The first vaccination was for what disease?
small pox
What are the two types of lymphocytes?
B&T
For Rh, a second exposure is very serious. Why is a first exposure, like a
transfusion of the wrong blood group, bad in ABO blood groups?
there are already antibodies
A bacterium is engulfed into a vacuole in a phagocytic white blood cell. What
cellular organelle, a bag of acid hydrolases, fuses with this endosome to
destroy the bacterium.
lysosome
Like neutrophils, monocytes infiltrate the injury site, attracted by
chemotaxis. What is the difference in timing?
monocytes are later
Considering how much fibrin is around when clotting is needed, how come fibrin
does not make blood clot all the time?
unless cleaved by clotting cascade, fibrinogen is inactive
Macrophages are derived from what type of white blood cell?
monocytes
Why are the prospects for worldwide elimination of flu by immunization more
elusive than for smallpox or polio?
evolution of virus in alternative hosts like birds and pigs
Antibodies produced by plasma cells are ineffective against infected cells.
What specific type of lymphocyte destroys such cells loaded with foreign
bacteria or viruses?
killer (cytotoxic) T lymphocytes
Class 1 & 2 MHC (major histocompatibility complex) molecules are expressed
on the surfaces of various cells. Why is it almost guaranteed that yours are
different from mine?
many genes, many alleles of each
If type A red blood cells are transfused into a type B person, antibodies in
the type B blood will cause the red blood cells to clump. What is this clumping
called?
agglutination
What is the chemical signal that the helper T cell uses to cause the
appropriate type of killer T cells to proliferate?
interleukin 2
Which specific antibody crosses the placenta to give the baby the mother's
immunities early in life?
IgG
In what way is IgG different from IgM with regard to the placenta and blood
groups?
IgG for Rh cross, IgM for ABO not cross
"Monocytes have a late chemotaxis and form macrophages." Translate.
these white blood cells are attracted to the site of injury after
polymorphonuclear granulocytes and further develop into big phagocytic cells
Which specific type of white blood cell is depleted in AIDS (acquired immunodeficiency
syndrome)?
CD4-expressing (helper)
Why are lysosomes an important part of phagocytic leukocytes?
they merge with endosomes to digest them
What kind of immunity does RhoGAM confer in the treatment for Rh- mothers?
passive
Why is there a major difference between small pox and flu (influenza) with
respect to the prospects for total elimination of the disease from the
worldwide human population?
flu evolves and has alternative animal hosts
What purpose does IgD on the surface of B cells serve?
it is the antigen receptor
An allergen binding to IgE on the surface of mast cells causes the release of
what substance from its granules?
histamine
Class II MHC (major histocompatability complex) is expressed only on
macrophages and B lymphocytes. What about class I?
all cells, involved in attack on infected cells
Why is AB the universal recipient?
no A or B antibodies
Neutrophils, eosinophils and basophils are all white blood cells. Name a
different type of white blood cell.
monocytes, lymphocytes (B and T)
Why is there so much variability in the MHC (major histocompatability complex)?
20 genes, 50 alleles each
Why is it beneficial for the infant that IgG crosses the placenta and that IgA
is in mother's milk?
passive immunity from mother
CD8 vs. CD4 coreceptors distinguish what types of cell?
Killer vs helper T cells
What is agglutination as it applies to antibodies and the blood groups?
antibody causes cells to clump
We don't worry so much about blood type (ABO) of the fetus vs the mother, but
we do worry about Rh factor. Why the difference?
IgM does not cross placenta, IgG does
For what is IgE most relevant?
allergy
How can MHC be so variable?
20 genes 50 alleles each
If all goes as "intended," what happens to a bacteria-containing
endosome in a white blood cell?
becomes secondary lysosome after merging with primary lysosome (etc.)
Which blood cells are the precursors of macrophages?
monocytes
Some bacteria come in through a small skin injury. How do phagocytitc cells get
from an intact capillary to the site of the injury?
chem,otaxis, slither between endothlial cells
What is the major product exported from the B lymphocyte?
antibody molecules
What type of cells are the memory cells that can jump-start the response to the
next exposure to an antigen?
B lymphocytes
What kind of protein is the antigen receptor on the surface of a B lymphocyte?
antibody (IgD)
What is the difference between an epitope and an antigen?
epitope (antigenic determinant) is the small portion of the antigen to which
the antibody binds
How can an infant be immune to some diseases between birth and weaning?
IgG across placenta, IgA in milk
How would a blood count help to determine if you had a systemic bacterial
infection?
There are more neutrophils in bacterial infection
Explain what agglutination is using transfusion of type A blood into a type B
recipient as your example.
Antibodies would cause red blood cells to clump together
How can your immune system (conceivably) develop antibodies to every possible
epitope?
The genes themselves get spliced to make the many variable regions
Class 2 MHC on the surface of an antigen-presenting macrophage acts in
conjunction with (what?) on the surface of a helper T cell to activate it.
CD4
Why did AIDS, in the first few years, create a new "selection
pressure" against hemophiliacs?
before AIDS, the "environment" was one where clotting factor was
available through medical technology; after AIDS (before the blood banks were
better secured) this factor from multiple blood donors had a grim chance of
being infected
What does a phagocytic cell do to destroy a bacterium after it has
"swalled" it?
presumably the endosome with the bacterium fuses with a primary lysosome,
though some bacteria have evolved tricks to escape the endosome
"Monocytes have a late chemotaxis." Explain: either (1) later than
what? Or (2) just what do are they doing that is called chemotaxis?
1-neutrophils, 2-slither out between endothelial cells
In what way do different antibodies create different risks for the fetus,
comparing the ABO blood groups vs. Rh factor.
IgM not cross placenta but IgG does so 2nd Rh+ fetus is a problem for an Rh-
mother unless she has antibodies after the first is born
"Clone" is a term applied in the discussion of the development of
plasma and memory cells from B lymphocytes. What is that term meant to imply?
tha after a B cell is subjected to a particular epitope, a bunch of plasma and
memory cells responsive to that epitope will form
To what fraction or portion of an antigen does an antibody bind?
epitope, 5 to 15 amino acids (also groups attached to them) near eachother
Address an infant's immunity answering either (1) what kind of antibody gave
the newborn some of the mother's immunities at the moment of birth, OR (2) what
kind of antibody from the mother can prolong the infant's immunity (that the
mother had developed) for some time after that?
(1) IgG, (2) IgA
Address allergies with either (1) what kind of antibody is released from a
plasma cell, (2) to activate what kind of receptor on the surface of a mast
cell, OR (3) to release what substance from a mast cell.
(1) IgE (2) IgE receptor (3) histamine
CD8 coreceptor on a killer T cell acts in conjunction with (what?) on the
surface of an infected cell to destroy that cell.
Class 1 MHC (also viral antigen)
this page was last revised 7/28/09
** The somatic sensory and motor systems
Sensory and motor systems
Text: selections from Chapters 8 & 10
Personal reflection
Though broadly trained, my Ph.D. and my
first job (Assistant Professor) were in psychology. It was only in 1979 that I
moved to biology. Long ago, I learned of certain brain studies after
transecting the spinal cord in animals: the encephale isole, French for the
isolated brain. This is much like the preparatioon the Nobelist Sherrington
used for studies of spinal reflexes. I came to view studies above the
transection as psychology and below as physiology. Thus, to me, the
somatosensory system and the motor systems seem more in the jurisdiction of a
physiology course than special senses such as vision & audition.
Review
Fig. 8.28
Spinal cord has white matter (myelinated tracts)
and
Gray matter (cells and synapses)
Dorsal root ganglion has cells for sensory input
Ventral root has output (motor) axons
Unit of behavior is reflex
In addition,
Sensory information goes to brain
and
Motor output comes from brain
and that is what this outline is about
SENSORY
Touch (somesthesis) and motor representations in the cerebral cortex
Fig. 8.6
"This is your brain. This (colorful diagram) is your brain in BL A260
class"
Brain, central sulcus with post-central gyrus (somatosensory projection)
and pre-central gyrus (motor area)
Many other aspects of "localization of function" for cerebral cortex
are shown here:
auditory area, visual area, Broca's area (speech)
Note also the cerebellum, an area devoted to motor coordination.
General and historical
A very compelling sense, from the pain of a tooth ache to the ecstasy of an
orgasm
There has been an emphasis on submodalities (qualities such as pain vs. hot),
where modalities refers to different senses like vision and audition
von Frey (around 1900) - punctate sensitivity - touch forearm with pencil,
sometimes feels cold, sometimes feel pressure.
This approach overemphasized correlation of histoloogical receptor type with
sensory experience.
It fit in well with Muller's (mid-1800's) "doctrine of specific nerve
energies" - in which, if the ears were made to feed in through the optic
nerve, sounds would be experienced as visual sensations because the quality
comes from the nervous system not the physics of the stimulus.
The present view of receptors and axons depends more on nerve type and
adaptation, and the central projection (axon type [A myelinated, C
unmyelinated] pathway [dorsal columns = lemniscal vs anterolateral =
spinothalamic) is critical.
Receptors in the skin
Fig. 10.4
Cutaneous receptors
The different types of receptors (in general, free nerve endings and encapsulated):
Free nerve endings
for pain, temperature and crude touch
Pacinian corpuscle - rapid adaptation
Lowenstein - peel to show layers make rapid adaptation
very sensitive, very large receptive field (area which, if stimulated, will
affect the receptor [or higher order sensory nerve]
vibration - 250 - 300 Hz
here is a Pacinian
corpuscle from our histology course
Meisner's corpuscles are fast but not as fast as Pacinian
encapsulation is with Schwann cell layers
most common receptors of fingers, palms and soles
smaller receptive field
"feeling" - active touch - would use fast as finger moves across
textured surface
Merkel's disks are slow and have a small receptive field and are for light touch
finger tips, lips and genitals
static discrimination of shape
Not in diagram
Ruffini slow - large receptive field -
sensitive to stretching in deep skin, ligaments and tendons
Krauss in lips and genitals (dry vs mucous skin)
warm and cold
a person can feel a difference of 0.01oC
relation to body temperature
(cold have additional peak at high temp - paradoxical cold -
pins and needles)
cold related to menthol
hot related to capsaicin
Nociceptors
some mediators of pain are in sting venoms
Also tissue damage substances: serotonin (platelets), prostaglandins,
leucotrienes, histamine from mast cells, substance P , bradykinin from blood
borne precursor
enzyme from injury, receptor is chemoreceptor
nociceptors are in many places, but not in brain, hence brain surgery under
local anesthesia used im mapping studies in humans by Penfield
Spinal cord
Fig. 8.24
input into spinal cord
(does not include face & head which enter via cranial nerves [trigeminal])
LEFT SIDE OF FIGURE
Lemnicsal system is for localized touch.
Lower limbs are handled medially in fasciculus gracilis.
Upper limbs are lateral in fasciculus cuneatus.
ipsilateral projection
First nucleus is in lower medulla
There is a cross-over, medial lemniscus and then the next nucleus is in the
thalamus.
In projection to the brain, there is processing - lateral inhibition to sharpen
spatial localization
If you tap your forearm, there are big waves but you feel localized touch.
RIGHT SIDE OF FIGURE
spinothalamic for pain and temperature
with synapse and decussation at entry point.
There are separate tracts in spinal cord.
The lateral portion is for pain and temperature.
The ventral (anterior) part is for gross tactile sense.
Hence the nomenclature "anterolateral."
Touch can inhibit inhibit pain (a hard touch to a door knob makes an electric
shock less annoying)
A half spinal cord injury would cause contralateral loss of spinothalamic below
injury and ipailateral loss of lemniscal.
Brown-Sequard syndrome include motor (ipsilateral impairment)
referred pain for viscera is interseting
notably, blatter stretch receptors localize pain to genitals
heart attack in neck and left arm
Brain
TRANSPARENCY (from intro book)
Just to show you that the material in your next transparency can also be found
in the freshman biology book.
Fig. 8.7
RIGHT SIDE OF FIGURE
sensory magnifications
Penfield - homunculus
MOTOR
Motor systems
LEFT SIDE OF FIGURE
topographic map of motor cortex- compare with corresponding sensory homumculus
work by neurosurgeon Penfield, note relative "magnifications"
toes (thought to curl with sexual excitement) in motor cortex across from
genital projection in postcentral gyrus.)
Fig. 8.25
Pyramidal system with corticospinal tract
Corticospinal tract Pyramidal motor system (75-90% crosses) 10 to the 6th axons
named because it goes through pyramids on ventral medulla
(though it might have been named from pyramidal shaped neurons in layer V incl.
Betz cells)
lateral and anterior pathways
Initiation of voluntary motor movements
output for face and upper body via facial nerve (and trigeminal, vagus,
accessory, hypoglossal)
Basal ganglia (nuclei)
Fig. 8.11
Not just motor cortex, but huge parts of cortex feed to basal ganglia (and
cerebellum).
Extrapyramidal (because it lies outside the pyramids)
caudate + putamen = striatum (striated because strands of internal capsule make
it look striated)
putamen + globus pallidus = lentiform nucleus [lens shaped] (see sheep brain
horizontal section)
Fig. 8.21
inputs to basal nuclei
substantia nigra (nigrostriatal dopamine system)
(also in medial forebrain bundle [through lateral hypothalamus] is the
mesolimbic dopamine system.)
outputs from basal ganglia
The globus pallidus is a relay nucleus for the caudate and putamen and so is
the subthalamus.
To VA/VL complex of thalamus to motor cortex
Disorders
Parkinson's see synapse
lecture
Huntington's (1872) disease (chorea) choreoathetosis
Dominant late onset - many interesting genetic counseling issues. The Folk
singer Woodie Guthrie died of Huntingtons. There is a big family tree derived
from Venezuela near lake Maracaibo
On post-mortem, degeneration of putamen and caudate is observed.
It is on short arm of chromosome 4
1983 and since: cloning -CAG repeat (polyglutamine repeat), 15-34 (normal)
-> 42-66 (Huntington's)
Other trinucleotide repeat diseases: fragile X syndrome, myotonic dystrophy,
and others
sometimes they get worse from generation to generation (anticipation)
in some ways, Huntingtons is the opposite of Parkinsons in that circuit has
thalamus increasing excitation to cortex.
Cerebellum
Dysmetria (cannot approach target), ataxia, intentional tremor if cerebellar
damage
cerebellum highly developed in electric fish
cerebellum is involved in rhythmic activity and plasticity
An additional decussation makes it so that cerebellum controls the ipsilateral
side of the body.
Questions from 2004 - 2008 exams that relate to this outline
Basal nuclei (caudate, putamen, and globus pallidus), part of the
extrapyramidal motor system, output through the thalamus to where?
the precentral gyrus
Faciculus cuneatus and fasciculus gracilis are part of what system?
lemniscal (for fine touch)
The gene (or gene product) of the gene that is abnormal in Huntington's chorea
has a variable number of what?
CAG (glutamine)
Where is the decussation (cross over) of the lemniscal system for localized
touch?
in medulla
A cell in the precentral gyrus whose axon is part of the corticospinal tract
makes its first synapse on what cell?
spinal motor neuron
What is the function of the postcentral gyrus?
primary somatosensory projection
What is mediated by the spinothalamic (anterolateral) system that decussates at
the level it enters the dorsal root?
pain and temperature
What are cells in the dorsal root ganglion used for?
somatosensory input to spinal cord
What property do the layers of encapsulation of a Pacinian corpuscle confer?
rapid adaptation
Between the tract called the medial lemniscus and the postcentral gyrus, there
is a synapse in what famous "relay station?"
thalamus
"The left half of the brain is for the right side of the body and
vice-versa." Is this conventional wisdom true for pain and temperature as
well as for fine touch?
yes, both, though crossings are at different levels
What is the function of the precentral gyrus?
voluntary motor initiation, motor cortex
Why is the anterolateral system so named (where is it?) and what is it used
for?
location between anteriot (ventral) and lateral in spinal cord white matter,
pain and temperature
Why is Huntington's disease sometimes called "chorea?"
chorea refers to jerky movements
Relate the expressions "triplet repeat" and "polyglutamine."
extra CAG's (nucleotide sequence) code for a string of glutamines (amino acid)
Where does a cell in the precentral gyrus make its first synapse?
Spinal motor neuron
In terms of localization of function of the cerebral cortex, what is the
function of the postcentral gyrus?
somatosensory projection
How would the protein product of the Huntington's disease gene compare for
someone without vs. with the disease?
more glutamines (amino acids) in a row with because of CAG triplet repeat
The output of the motor cortex (precentral gyrus, pyramidal system) goes all
the way to the spinal motor neuron. By contrast, where do basal nuclei
(extrapyramidal system) feed to?
thalamus, motor cortex
"That area of the skin, if deformed, that affects the response of one
specific Pacinian corpuscle." What is this called?
receptive field
Serotonin is a mediator for nociceptors. Name another.
prostaglandins, leukotrienes, histamine, substance P, bradykinin
The spinothalamic system for pain and temperature is also called the
anterolateral system. Why (does it have this other name)?
tracts are in ventral (anterior) and lateral parts of white matter in spinal
cord
Between the pain receptor and the lateral spinothalamic tract, where is the
first synapse?
in dorsal horn of spinal cord gray matter
Face and hand occupy about half the map of the motor cortex (precentral gyrus).
How was this map determined?
stimulate brain of awake surgery patient and see where movement is
Earlier this semester, you learned that the substantia nigra does not make
enough dopamine in Parkinson's disease. How does the substantia nigra feed into
the motor system?
connects to striatum in extrapyramidal motor system
Voluntary motor movements for the face go out through cranial nerves. By contrast,
what tract carries motor output from the motor cortex (precentral gyrus) to the
lower part of the body?
corticospinal, pyramidal
Where is the cell body for the somatosensory receptor cell?
right outside the dorsal root of the spinal cord, dorsal root ganglion
What is the function of the postcentral gyrus?
somatosensory projection
Why would it be useful to have a touch receptor that is sensitive for
vibration?
for active feeling
Where is the first synapse in the lemniscal input?
in the medulla (fasciculi gracilis and cuneatus)
What does it signify that the hand is as large as the arm on the motor cortex?
magnification where motor movements are more dextrous
In comparison with the extrapyramidal system, what is corticospinal spinal
tract called?
pyramidal system
Where does the globus pallidus feed to?
to thalamus to motor cortex
The dopamine system is called "nigrostrital." Give the real names of
the areas for which it got this name.
substantia nigra, striatum
"Nociceptors are chemoreceptors." Explain.
chemicals at the site of injury like bradykinin stimulate them
Where is the first synapse in the anterolateral input?
right in the dorsal horn
Why would half the children of a Huntington's victim be expected to get the
disease?
autosomal dominant
Huntington's disease is called a "triplet repeat disease." Triplets
of what?
nucleotides
Why does a textbook have a lateral view of the cerebral cortex which has
different locations colored differently?
to emphasize localization of function, for instance sensory areas for different
modalities
"A rapidly adapting pressure receptor is useful for active touch."
Explain.
As you feel a textured surface, that receptor is vibrated
For the anterolateral system, a cell in the dorsal horn of the gray matter of
the spinal cord makes its synapse (where in the brain?).
thalamus
(Refer to the previous question.) "This anterolateral system ultimately
projects to the same part of the cerebral cortex as another system. Answer
either (1) What is this part of the cortex called? Or (2) What is this other
system? (name, location in spinal cord, OR function will suffice).
(1) motor cortex = precentral gyrus (2) lemniscal carried in dorsal columns
mediating fine touch
"The corticospinal tract is for voluntary motor output." What about
the face?
Cranial nerve 5 trigeminal
"Huntington's disease shows 'anticipation,' getting worse from generation
to generation." What changes (molecularly)?
Nucleotide triplet CAG (that codes for glutamine
WHY (note, I am just asking why) would a half spinal cord lesion affect senses
mediated by spinothalamic vs lemniscal systems below the injury differently?
Where they cross over is different, spinothalamic below the lesion, lemniscal
above
62. How was the map of the postcentral gyrus obtained?
Gently electrically stimulate and ask the person where (s)he feels it
63. "The thalamus is a relay (more than a relay!) for sensory and motor
systems." And yet the corticospinal tract went right past the thalamus
without making a synapse. In what system, then does the thalamus have motor
synapses?
Extrapyramidal - basal ganglia feed back to motor cortex via thalamus
this page was last revised 8/3/09
**Sensory systems
The Senses
Fox, part of Chapter 10, figure from chapter 8
General
There are 5 "special" senses
touch (somesthesis) - already covered in previous outline
taste (gustation) - next (this outline)
smell (olfaction - after taste (this outline)
hearing (audition) - a big topic, next outline
sight (vision) - a huge topic, the outline after next
Taste (Gustation)
for chemicals dissolved in water
Gustation - chemicals - Many "flavors" are smell
Hanig (1901) - preferential localization:
sweet - tip of tongue
salt - front sides of tongue
sour - back sides of tongue
bitter - back middle of tongue
On tongue:
Papillae: Circumvallate (preference for quinine), foliate, fungiform
(preference for sucrose)
also receptors in epiglottis
epiglottis via nerve X (vagus), circumvallate (9 of them) via IX
(glossopharyngial), others via VII (facial)
Fig. 10.7
Several types of papilla including the circumvallate papillae on the back of
the tongue, shown in this picture from our histology course
Within each papilla are numerous clusters of cells called taste buds shown
in this histology picture. support cells and sensory cells
Note that there are taste "blindnesses" Ptc = phenylthiocarbamide,
taster is dominant and nontaster
Use taste vs. non-taste to screen for G-protein coupled receptors (M. Barinaga,
Family of bitter taste receptors found, Science 287, 2133-2135, 2000)
Fig. 10.8
generally, channel or G-protein linked receptor ultimately increasing calcium
somehow for synapse
note receptor does not have axon
salt - Na+ channel opens (depolarization)
sour - pH sensitive channel closes (depolarization)
sweet - G-protein linked cAMP close K+ channel - depolarize
bitter -G-protein cascade
umami (glutamate) - and amino acids, channels as well as G-protein cascade
In each case, Ca2+ involved in vesicle release
Taste Projection
(much simpler than for olfaction)
Gustatory nucleus in medulla,
there to thalamus and then to sensory cortex, overlap to touch area -
postcentral gyrus
also from medulla to hypothalamus
Smell- Olfaction
There are unusual primaries like aromatic and putrid , there may be many
primaries, although mixtures give a single perception confounding the ability
to define primaries
Relative to other senss, receptors difficult to stimulate
Even more than with the sense of touch, olfaction is related to motivational
"affect"
The sense of smell is especially important in other animals (dogs)
Fig. 10.9
Anatomy of olfactory epithelium.
Note: the receptors are neurons with axons, unlike for taste
Receptors are ciliary, with cilia in mucus
Transduction - G protein coupled receptor via adenylyl cyclase
There is a specialized olfactory alpha subunit of the G protein (Golf)
Na+ - Ca2+ channel is like that of photoreceptor in that cAMP acts as a ligand
to open the channel from inside the cell
Ca2+ opens Cl- channel
there is also a pathway involving PLC and IP3, but which is otherwise similar
in the background, there is a Na+/Ca++ exchanger
G-protein coupled receptor is very variable (there may be thousands, meaning
that olfactory receptors contribute predominantly to diversity of
G-protein-coupled receptors) and has specific variable regions
Axel and Buck won the 2004 Nobel prize
(Physiology and medicine for this contribution)
Projection
Glomeruli - > Mitral cells -> lateral olfactory tract
Fig. 8.15
Olfaction is a complex sensory system in part because of the CNS projection to
amygdala, hypothalamus, hippocampus) , areas called Limbic system
Also
There are senses outside the 5 special senses
Vestibular sense
Fig. 10.13
note proximity with cochlea (for hearing)
utricle and sacculus linear motions
3 semicircular canals - rotations
TRANSPARENCY Fig. 10.15
stones (otoconia) provide mass for bending in utricle and sacculus
TRANSPARENCY Fig. 10.16
cupula displaced as semicircular canal fluid is displaced
transduction
TRANSPARENCY Fig. 10.14
hair cells (also for audition) [mechanoreceptor]
kinocilium (real cilium)
plus about 30 stereoocilia
mechanoreception assisted by tip links - depolarization if move toward
kinocilium
hyperpolarize if in opposite direction
Test questions from 2004 - 2008 relating to this outline
What type of molecule must come in many varieties to mediate the richness of
olfaction you enjoy?
G protein linked receptor
Where is the first synapse in the olfactory system?
olfactory bulb
What is detected when endolymph bends the cupula?
head rotation
What does the term "umami" refer to?
a taste, glutamate
Which sensory system projects to the limbic system, including the amygdala?
olfaction
After a bitter tastant causes Ca2+ to increase in the cell, what does that Ca2+
do?
cause transmitter release
Out of the 5 special senses, which one does not have a localized area of the
cerebral cortex as its final projection?
olfaction
About how many different G protein coupled receptors are involved in human
olfaction?
1000
In addition to the vestibular sense, which utilizes hair cells where
"hair" refers to stereocilia?
audition
All taste cell types, by one mechanism or another, have an influx of Ca2+. What
process does this increased cytoplasmic calcium mediate?
synaptic vesicle release
A portion of the brain hypothesized to be involved in olfaction, emotion, and
memory.
limbic system (or any part of it)
What is PTC (phenylthiocarbamide) and what did it reveal about sensory
transduction?
a substance that tastes bitter and helped in the isolation of the G
protein-coupled receptor
How is the richness of olfactory experience coded in the genes for olfactory
receptor molecules?
a different gene for each G protein-coupled receptor, very variable
Upon stimulation, for each taste primary, cytoplasmic Ca2+ increases. What is
it used for?
for release of transmitter vesicles
The ciliary receptor cells in the nasal epithelium have axons that terminate
(where)?
olfactory bulb (first cranial "nerve")
What brain center involved in motivational aspects of hunger does the olfactory
bulb project to?
hypothalamus
There are three nerves that carry taste information to the brain. These three
nerves are among a famous set of about a dozen that are collectively referred
to as (what)?
cranial nerves
In olfactory transduction, what does cAMP do to affect the electrical
properties of the receptor cell membrane?
cAMP is the ligand that gates the cation channel from inside the cell
Where are the sense organs that monitor your head position to keep your eyes
upright for slight tilting of the head?
near the cochlea (for hearing)
In what way does the tastant for umami relate to a central nervous system
excitatory neurotransmitter?
glutamate
About how many olfactory receptor molecules does a human have?
500-1000
In addition to G protein-coupled receptors, what is the other type of taste
receptor molecule?
channel
In taste receptors, Ca2+, mediating transmitter release, comes from either
outside the cell or (what subcellular structure?)?
endoplasmic reticulum
Where do olfactory neurons make their synapses?
olfactory bulb
What are the "hairs" of hair cells, and what happens when they are
bent?
cilia (stereocilia), open or close channel, depolarize or hyperpolarize
In what way are calcium ions essential for the signaling of the taste receptor
cells to the cranial nerves?
mediate exocytosis of vesicles
In some cases, taste receptor molecules are channels. Alternatively they are
(what?).
G protein coupled receptors
Why do olfactory axons seem to zig-zag rather than just connect to the closest
glomerulus? (That pertained to yellow and green receptors, as colorized in your
figure, connecting to yellow and green glomeruli.)
presumably, each glomerulus receives only from receptors expressing the same
receptor
In the G protein-coupled receptor cascade in the olfactory cell, how did the
cAMP affect the cell's response?
ligand close K+ channel
Describe the receptor cells of the vestibular system with respect to their (1)
structure, or (2) the type of stimulus that excites them.
(1) "hair" cells with stereocilia, mechanical
On the back of the tongue, taste buds are found on what larger structure (hint,
nine of them, and the nerve projects by the IX cranial nerve, the
glossopharyngeal).
Circumvallate papillae
65. In terms of the respective molecular biology of transduction, why is
olfaction a much richer sense than taste in humans?
There are maybe a thousand receptors for different primaries
this page was last updated 8/3/09
**The audition lecture
Audition
Fox, part of Chapter 10 and one figure in chapter 8
Physics of Sound
(not all of this is in the book)
Intensity dB = 20 log (pressure 1/pressure2)
standard is 0.0002 dynes/cm2
Threshold amplitude of vibration is 10 to the -11 m (10 pico meters)
waves of compressions and rarefactions of air (must have medium) described by
sine wave
Frequency Hz cycles per sec
vibration - 20 - 20,000 Hz, above which is ultrasound .
Audibility curve - Intensity [dB] vs log (freq) [Hz] very sensitive
Ear
Fig. 10.18
Ear structure
pinna, eardrum=tympanic membrane, ossicles, cochlea, part of nerve VIII =
cochlear nerve
Fig. 10.19
hammer, anvil, stirrup=malleus, incus, stapes - to match impedance of air ->
fluid
Eustachian tube
oval window is "inner ear drum"
20:1 "amplification" tympanic to oval
Fig. 10.20
Since the cochlea is wound like a snail, a section through it shows repeated
structures
Fig. 10.22
higher magnification, most importantly basilar and tectorial membrane
also inner hair cells and outer hair cells
Auditory transduction
hair cells on basilar and tectorial membranes
3,500 inner hair cells
many more outer hair cells
Bend as basilar membrane vibrates relative to tectorial membrane
(repeated from vestibular apparatus lecture)
kinocilium (real cilium, missing in post-natal human hair cells)
plus about 30 stereoocilia
mechanoreception assisted by tip links - depolarization if move toward
kinocilium
hyperpolarize if in opposite direction
Threshold displacement is about 0.3 nm
go back to Fig. 10.20
perilymph is fluid of scala vestibuli and scala tympani is like CSF - bathes
baso-lateral hair cell
High K+ in endolymph of scala media (bathing hairs)
stria vascularis (endothelium lining scala media) pumps ions to produce this
unusual extracellular fluid
thus when channels open, K+ comes into cell
endocochlear potential endolymph 80 mV more + than perilymph
Frequency discrimination
At about 1000 Hz, you can tell the difference of a few Hz. This is explained by
Helmholtz's place theory as modified by lateral inhibition as described in
Bekesy's (1961) Nobel Prize
winning work on "physical mechanism of stimulation within the
coclea."
At low frequencies, frequency discrimination is better explained by
Rutherford's telephone theory. Here, frequencies to both ears can cause neural
impulses that stay true to the frequency so that beats can be from neural
comparison from the two ears.
Fig. 10.21
Vibration of basilar membrane is mapped by tonotopy
fluid vibration at oval window through helicotrema
Low frequencies vibrate mostly near helicotrema
High frequencies vibrate mostly near oval window
But the localization is crude
Lateral nhibition refines localization on the way to brain so that cells in
brain respond to only a few frequencies
Fig. 10.25
Frequency map on cortex
Frequency discrimination at low frequencies
there was another theory, Rutherford's "telephone" theory
phase-locking gives volley principle up to 4 kHz
Projection
Auditory nerve to dorsal and ventral cochlear nucleus - no crossing
Several synapses on the way to the Thalamus
Fig. 10.24
Thalamus to auditory cortex
Auditory localization
difference in time of arrival and intensity (in big headed animals) [human 700
micro sceond difference]
(speed of sound 1087 ft (331 m) / s in air)
Localization up and down does not rely on 2 ears,may relate to pinna
small-headed animals are extraordinary
Exam questions fron 2004 - 2008 that apply to this outline
Helmholtz's place theory for frequency discrimination refers to place on what
membrane?
basilar
Because the perilymph cannot be compressed, pressure applied at the oval window
is released where?
round window
If the pressure is 0.002 dynes/cm2, 10 times the standard for audition (0.0002
dynes/cm2), how many dB is the sound?
20
The stapes drives vibrations to what structure?
oval window
If two audio oscillators set to about 1000, playing through loud speakers, give
5 beats per second, what would you perceive if you heard one then the other
sequentially?
you would hear distinctly different pitches
In addition to the vestibular sense, which utilizes hair cells where
"hair" refers to stereocilia?
audition
For people, in addition to intensity of sound for one ear vs the other, what
contributes to auditory localization?
time of arrival
What does "tonotopic" refer to with respect to organization of the
cortical projection for hearing?
different frequencies project to different places in an organized way
A log unit is an order of magnitude, i.e. 10 x. How many dB per log unit?
20
Tip links between stereocilia contribute to channels responsible for what kind
of stimulation?
mechanosensation, or hearing, possibly K+
If a certain sound is 20 dB louder than another sound, how many times as loud
is it?
10 x (one log unit)
Why is it reasonable to propose that a sound might arrive at the two human ears
at different times?
speed of sound is finite (slow) and head is big
Why was it useful to hold the tuning fork and loud speaker to one ear
simultaneously before demonstrating frequency discrimination by holding them to
one ear sequentially?
beats prove that two stimuli differ by only a few Hz
"Hairs" on hair cells bend when the basilar membrane moves with
respect to what other membrane?
tectorial
A young human can hear frequencies from about 20 Hz up to about (what)?
20,000
In what way is K+ particularly relevant to auditory transduction?
K+-rich extracellular endolymph in scala media (secreted by stria vascularis)
makes it so that, when channels open, K+ comes into cells
Helmholtz proposed that different frequencies stimulated different places along
the basilar membrane. In what way(s) was his place theory confirmed or
contradicted?
true, but localization is crude, lateral inhibition corrects for this
The vestibular apparatus shares a nerve to the brain with what special sense?
auditory
"There is tonotopic localization in the auditory cortex." Explain.
different frequencies at different locations in an order
"The audibility curve extends from about 20 to 20,000 Hz." What would
be the most obvious difference (from this statement) among the people in the
room where your physiology course was taught.
your professor would have an age related loss at higher frequencies
Why is the round window useful, in fact necessary?
to release pressures applied to oval window since fluid cannot be compressed
What is compared that would allow you to tell which side of your head a sound
is coming from?
inputs from the two ears
How is it that K+ moves in, rather than out, through channels in auditory hair
cells?
an unusual extracellular fluid (endolymph) is high in K+
About how many Hz is the just noticeable difference at 1000 Hz?
2
Twenty times the log of one pressure divided by 0.0002 dynes/cm2 tells us what
property of sound?
intensity
There is a cut-off of (what? - give number and units) between "sound"
(that humans can hear) and ultrasound (such as dogs and bats can hear).
20,000 Hz
"Helmholtz was correct in general but wrong in the details" (about
frequency discrimination). How so?
Bekesy demonstrated that different freqencies stimulated different places, but
more crudely than Helmholtz imagined. (need latreral inhibition to process)
The sound may arrive at one ear 700 microseconds before the other ear. Answer
either (1) How can this be? Or (2) Why is that useful?
(sound has a finite (slow) speed considering the size of the head
Movement of the organ of Corti relative to (what adjacent membrane?) causes the
"cilia" of auditory hair cells to bend.
tectorial
K+ comes in through the auditory cell channel. Now, wait a doggone minute. How
did that happen?
b/c K+ is high, which is unusual, in the extracellular fluid (endolymph)
this page was last revised 8/3/09
**The vision outline
Eye and Vision
Fox, a substantial part of Chapter 10
Review
Vision is usually covered everywhere, and Freeman has the topic
TRANSPARENCY (intro book) eye and retina structure
TRANSPARENCY (intro book) spectrum and spectra for the 3 cones that mediate
color vision
Eye structure
Fig. 10.27
the eye picture of an ophthalmologist's office
cornea, iris, pupil, conjunctiva, sclera, extraocular muscles
lens, aqueous (anterior chamber), vitreous (vitreous chamber), retina, fovea,
optic n.
there is a blind spot where the optic nerve exits
Fig. 10.31
Here is a picture showing focus of an arrow up-side-down on the retina, trivial
except that is shows that most of the bending is at the cornea where the change
of index of refraction at the air-cornea interface is very large.
Refractive Disorders
Fig. 10.35
refractive errors
diopters - reciprocal of focal distance in m
cornea is 0.024 m, 42 diopters
Emmetropia-normal,
Hyperopia-far-sighted, need convex lens,
Myopia-near-sighted, need concave lens, involves abnormal elongation of the eye
visual angle, acuity - Snellen eye chart - 20/20 is seeing letter 5 min (1/60
degree)
Accomodation and presbyopia
Fig. 10.34
Accomodation
loss of accomodation with age explains Presbyopia
Benjamin Franklin developed bifocals
This is a difficult concept and the best figure I've seen to explain it:
If ciliary muscle is relaxed, ligaments are tight and lens is stretched flat
If ciliary muscle contracts, ligaments have slack and lens relaxes to greater
bulge for near vision.
Here, in an albino
rabbit eye dissection, you can see the suspensory ligaments of the ciliary
muscle.
Other disorders:
Glaucoma - pressure is too high because aqueous humor does not drain well,
ganglion cells die, treated with drops or surgery
Floaters in vitreous especially in myopia
Diabetic retinopathy blood vessels overgrow, leak, blast holes in retina with
laser decreases angiogenesis
Cataract - lens becomes opaque, remove and often replace with intraocular lens,
made of polymethyl methacrylate, known to be tolerated since pieces from
airplane visors would nlodge in pilots under fire (and since about 1988, these
have been doped with UV blockers)
Retinitis pigmentosa is tragic, people can see when young, lose rod vision
(tunnel vision [ring scotoma] because rods are in mid-periphery).
Rods go first and eventually cones which is strange if rod molecules are
mutant.
There are autosomal and X-linked types, dominant and recessive.
There are other genetic degenerations and stationary (not progressive)
blindnesses are in molecules of transduction cascade (book only mentions
missense mutations in opsin) as well as in other rod and cone molecules.
There is a web site where information relevant to the retina, especially
genetic causes of blindness, accumulates (site)
Age related macular degeneration may have an genetic basis too
Pupil
Fig. 10.28
An interesting and related story has to do with dilation of the pupil.
Recall that atropine, a muscarinic antagonist, dilates the pupil.
That means that the parasympathetic nervous system constricts the pupil.
Recall that parasympathetic = cranio-sacral, and here the cranial nerve is the
occulomotor nerve (#III)
By contrast, the sympathetic n.s. dilates (in dim light), and the nerve has to
come up from the superior cervical ganglion (of the thoraco-lumbar system)
A bright light in one eye causes the other pupil to constrict too. (Try this in
front of a mirror with a flashlight.)
Neurologists can make use of information based on defects in the pupillary
reflex.
Eye structure
Fig. 10.30
"the eye is the window to the brain" -- physician can actually look
at CNS
For instance, increased crainial pressure (like from tumor) shows up as
papilledema
Optic disc is where optic nerve exits and blood supply enters and exits.
Fovea is high acuity cone vision.
Macula lutea is area where carotenoids (lutein and zeaxanthin) form
blue-blocking (yellow) filter.
Here is a picture a
friend (Lynette Feeney-Burns) gave me before she retired (in about 1990). It is
labeled "normal macular pigment - chow diet," and it demonstrates the
density of yellow pigment around the fovea in (presumably) monkeys fed a diet
adequate in carotenoids. Currently, it is known that the carotenoids lutein and
zeaxanthin are in nerve layers in the light path to the receptors of the fovea
(cones). We get these yellow-appearing caroteinois in our diet (e.g. from
spinach and corn). It is thought that they help to protect cones from damage
that may be induced by blue light. It was found that the concentration is
increased with dietary increases, and now lutein is included in multi-vitamins.
Here, in a sheep
eye dissection, you can see the optic disc. Retina is white, pigment epithelium
and choroid are black.
Rods and Cones
TRANSPARENCY (here is a pdf of this
transparency)
Hecht, Schlaar and Pirenne (1942) published a study that a human subject can
see a light so dim that 6-14 quanta were absorbed over a 500 rod area; that
means one rod can "see" one quantum.
Here are some calculations showing how to determine the energy of a photon
using Planck's constant (obviously very low).
I also roughly calculate to show that the threshold for audition is comparably
low.
Fig. 10.44
Photoreceptors- 125 million receptors 20/1 rods to cones
(converge on 1 million ganglion cells)
Adds to sensitivity of rods and to acuity for cones.
Retinal circuitry
Fig. 10.36
Retina is mounted backwards relative to the path of light
expands on the above figure with retinal wiring diagram:
Straight through: Photoreceptor -> bipolar -> "ganglion" cells
(whose axons form the optic nerve)
Horizontal interactions: Horizontal cells and amacrine cells
Pigment epithelium - melanin, vitamin A conversions, and phagocytosis of spent
photoreceptor membrane
rods concentrated off-fovea, cones on-fovea
Rod, peripheral vision, dim black and white, sensitive - "scotopic"
Very sensitive - 1 photon
Cone, fovea, color, acuity - "photopic"
Shown in rats, rods are supported by retinal
pigment epithelium
RPE: (1) melanin that blocks light reflection
(2) metabolism to provide 11-cis retinal (chromophore ofvisual pigment,
rhodopsin)
(3) phagocytosis and recycling of shed rod tips
Cells are postmitotic and the indigestible residue of the phagolysosomal system
is lipofuscin, a
fluorescent aging pigment, a topic on which I've done research.
Color vision
Fig. 10.42
spectral sensitivity of rods and 3 cone types
confirms Young -Helmholtz trichromatic theory
3 kinds of cone 420 530 560
3 kinds of cone opsins which are evolutionarily related in humans and OW
monkeys
green and yellow (middle and long wavelength) cone opsins are near each other
on X
(blue cone opsin is on human chromosome 7, rod on chromosome 3)
evolutionary bottleneck hypothesis color vision re-evolves after nocturnal life
(where adaptive pressure for cone vision is relaxed) early in mammalian
evolution
Red or green color blindness - on X, thus preferentially in males.
Blindnesses were thought to be from altered genes, but numbr of copies in human
population is variable, and cross-over accidents can even make chimeric genes.
Female "carriers" should actually be mosaics of color blind vs normal
retina because of Mary Lyon X-inactivation hypothesis
superfamily of G-protein-coupled receptors (7 transmembrane domain receptors)
Phototransduction
Fig. 10.39
light causes 11-cis retinal (aldehyde of vitamin A, retinol) to turn to
all-trans.
("retinene" - term used in book - is old fashioned)
George Wald 1967 Nobel prize
Fig. 10.40
The alpha subunit of transducin (the name for the G protein) activates cGMP PDE
(phosphodiesterase)
Less cGMP (ligand) and channel closes so cell hyperpolarizes since sodium
channel closes.
Fig. 10.41
This figure repeats the above point.
Because there are Na+ channels in the outer segment and a Na+-K+ ATPase in the
inner segment (where there are lots of mitochondria manufacturing ATP), there
is a dark current turned off in the light.
(Also shows how rod cell is a stack of disks with rhodopsin and other
transduction molecules)
Transmitter is released in dark - but less when light is on
Wiring
(and processing - my coverage here will be minimal)
10.45
Temporal retina does not cross at optic chiasm but goes to ipsilateral lateral
geniculate nucleus (part of the thalamus)
Nasal retina goes to contralateral LGN
At LGN, inputs from 2 eyes does not mix.
Projection to cortex where eye inputs mix for stereopsis, and processing for
contrast, moving lines, angles, etc takes place.
Superior colliculus (important for eye movement control)
My interests center around vision, so a visit to the research interests of my home page will
offer various topics about vitamin A, ultraviolet light, and Drosophila
mutants. The Biology Department has a vertebrate vision specialist, Judith Ogilvie. Dr.
Ariel in SLU's Pharmacology Physiology Department is one of my fellow
wizards in visual science.
Exam questions from 2004 - 2008 relating to this outline
What intracellular ligand, whose function is to open channels, is decreased
when light stimulates a rod?
cGMP
Energy equals Planck's constant times the frequency. Energy of what?
of one photon
For what population of people is macular degeneration most common?
elderly
What must be bound to the G-protein-coupled-receptor protein to make the
fully-functional rhodopsin molecule that absorbs light?
retinal
What happens to a rod's neurotransmitter release when light hits the rod?
decreases
The ciliary muscle contracts, in accomodation, to let you do what?
see up close
How does an eye care professional test for glaucoma?
poke the eye for a pressure check
In the dark, a current of Na+ ions flows from the sodium pump in the inner
segment through what in the outer segment?
channels
When an axon from a ganglion cell goes toward the brain in the optic nerve,
where does it first synapse?
thalamus
What layer at the back of the eye is black?
retinal pigment epithelium, also choroid
Some men taking Viagra (sildenafil) report impaired color vision. Why might
this be?
Viagra and phototransduction both involve cGMP
Where are the genes of the long- and middle-wavelength cone rhodopsins located?
X chromosome
Our gaze seems more relaxed for far vision even though suspensory ligaments are
relaxed for the lens to accomodate for near work. What does contract to change
the lens shape to see up close?
ciliary muscle
A current of Na+ in the dark along the rod is from the Na+/K+ pump in the inner
segment and what in the outer segment?
Na+ channel (or transduction machinery)
What specific cellular defect explains the tunnel vision (ring scotoma) of
retinitis pigmentosa?
rods degenerate
What is the only direct effect of light in initiating phototransduction?
cis -> trans isomerization of retinal
What kind of lens corrects for myopia (near-sightedness)?
concave
Which two rhodopsins used for human color vision are coded by adjacent genes on
the X chromosome?
middle and long wavelength (green and red [yellow])
Ganglion cells are killed from high eye pressure. What is this disorder called?
glaucoma
What layer of black cells supports rod outer segments by phagocytosis and
conversions of vitamin A?
retinal pigment epithelium
Epinephrine binds one G protein-coupled receptor (GPCR). What other GPCR, used
for vision, is a pigment that contains a form of vitamin A?
rhodopsin
As it applies to diabetic retinopathy, what is angiogenesis?
formation of new, fragile, blood vessels
Laser photocoagulation decreases angiogenesis. Here we are treating to prevent
further blindness from what disorder?
diabetes
Which side of the retina projects to the ipsilateral lateral geniculate body at
the optic chiasm?
temporal
Macular degeneration (MD) aflicts a certain population as reflected by the
"A" in the name (AMD). What population?
elderly (A=age-related)
Under what conditions are cGMP levels in the rod lowered?
when stimulated by light
Why is it inaccurate to consider a chromosomally normal woman to be be a
carrier for a recessive X-linked color blindness if the other chromosome is normal
(wild-type, dominant)?
mosaic of cells with one vs the other X functioning (Mary Lyon X inactivation
hypothesis)
Why does each eye have a blind spot?
there can be no receptors where the optic nerve exits
Why is cataract usually a less severe form of blindness than retinitis
pigmentosa?
there is straightforward surgery for cataract, whereas rods die and cannot be
recovered for rp
Scientific information has led to the decades-old conventional wisdom that
vitamin A is good for vision. Other than being the pigmented portion of
rhodopsin, where else do carotenoids come in to play, explaining why lutein is
a dietary supplement or a component in a multi-vitamin pill?
macular pigments protect fovea from blue light
Presbyopia is a defect in what process that affects most people over 40 years
old.
accomodation
Why is the cornea actually a stronger lens in the eye than the lens?
because of the big change in index of refraction from the air-cornea interface
Why is the rod depolarized in the dark (but not in the light)?
because cGMP opens sodium channels
The genes for the yellow- and green-light absorbing rhodopsins are near each
other on which chromosome?
X
The tip of the rod outer segment is sloughed off on a daily basis and
"recycled." Where does this cellular fragment go?
into retinal pigment epithelium
What does activation of the parasympathetic portion of the occulomotor nerve do
to the pupil?
closes
If your eye pressure is high, answer ONE of the following: (1) name of
disorder, (2) what is not draining appropriately, or (3) loss of what cells
mediates vision loss?
glaucoma, aqueous humor, ganglion cells
How can rhodopsin be mutant yet the patient still can see until retinitis
pigmentosa first presents in the teens or 20's?
in autosomal dominant, a normal recessive gene still expresses rhodopsin
Suppose you could stimulate a nerve to achieve the same effect as applying
belladonna alkaloids to the eye. What type of nerve would you stimulate?
sympathetic
A whole lot of rods converge onto each ganglion cell. What does this wiring
achieve?
sensitivity
What is lost in age related macular degeneration (AMD)? (Your answer can be
cellular or functional.)
cones, fovea; vision
If you stare straight at a mark (X), while a stimulus is presented to both eyes
to the right of the X, describe how the stimulus projects to the thalamus
(lateral beniculate nucleus).
temporal retina of left eye - ipsilateral projection; and nasal retina of right
(contralateral) to left
In the molecular mechanism from light absorption to hyperpolarization of the
rod, exactly what does 11-cis retinal do?
absorb light, convert to trans
Why would you see much better under water with vs without goggles?
keep the normal air-cornea interface (with the normal indices of refraction)
"The blind spot is about 15o off fovea in your nasal retinal field
(temporal visual field)." Translate.
location off axis is measured in angle, since the optic nerve exits 15o on the
side toward the nose, the inversion of the image would make it seem 15o off to
the side
"Visual experience can influence the progression of myopia." On what
basis can that statement be made with scientific authority?
research where the vision was distorted with goggles and the eye changed
"If the ciliary muscle is relaxed, the ligaments are tight and"
Finish this thought with respect to the shape of the lens and what that does
for vision.
lens flattens for distance vision
In the course a lifetime, a retinal pigment epithelial cell's ability to carry
out it's function might deteriorate. Why?
it fills with the indigestibloe residue of the phagolysosomal system
If you were convinced that blue light damages foveal cones, how might you alter
your diet starting now, while you are young, to delay age related macular degeneration
(AMD)?
eat veggies or vitamin pills with lutein or zeaxanthin
With what sort of methodology were scientists as early as 1942 able to come to
the conclusion that a rod can respond to one photon?
psychophysics, human subjects report if they can see calibrated lights
"A derivative of vitamin A is the chromophore of rhodopsin."
Translate.
vitamin A aldehyde is the light absorbing portion attached to the protein
Why would the evolution of red-green color vision on the X chromosome relate to
the richness of olfactory sensation?
it is a simple example of the evolution of G protein-coupled receptors
"Color normal is dominant, color blind is recessive, hence women can be
heterozygous carriers for green blindness." Why is this an
oversimplification?
they would be mosaics of cells with one or the other X functioning
Why is there an extracellular current from the rod outer segment to its inner
segment in the dark?
The channel letting Na+ in is in the OS, the sodium pump is in the IS
In terms of the channel gating, why does a rod hyperpolarize in response to
light?
the ligand (cGMP) that holds the Na+ channel open is broken down
You stare at an X with your right eye. Answer either (1) Where would the blind
spot be? (state this using the sort of terminology that might be used in
optometry) Or (2) How would you determine where it is while you are staring at
the X?
a certain angle (about 15 degrees) off axis (away from the fovea) in the
temporal visual field (nasal retinal field)
A muscle that mediates accommodation contracts. Answer either (1) What happens
for your vision? Or (2) What happens to the shape of the lens?
(1) better for near vision (2) becomes rounder
"The loss of vision is referred to as a 'ring scotoma.'" Answer (1)
What disorder? Or (2) Why is it a ring?
1-retinitis pigmentosa, rods (in mid-periphery) are lost
Which portions of the nervous system mediate constriction and dilation of the
pupil?
parasympathetic (constriction) and sympathetic (dilation)
One photon absorbed by rhodopsin elicits an electrophysiological response in a
rod. That plus what retinal wiring consideration makes scotopic vision
tremendously sensitive?
convergence of multiple rods to one ganglion cell
Why does the retinal pigment epithelial cell have so much to phagocytose?
tips of outer segments are shed daily
How (between New World monkeys and Old World monkeys) did there get to be (at
least) two color vision genes on the X chromosome?
unequal crossing over duplicated the gene
What is the only thing that light does directly to excite rhodopsin?
cause 11-cis to all trans isomerization of retinal
A light is switched on. What happens to the transmitter release from the rod?
decreased
The eye pressure is high. Answer either (1) What isn't draining properly? (2)
Death of what cell type would mediate vision loss? Or (3) What is this
condition called?
Aqueous humor, ganglion cell, glaucoma
Why would a person with my interests need to use Planck's constant?
Since it gives energy of a photon, it can assist in calculations of light
intensity
When an ophthalmologist looks at your retina, what is the second most
conspicuous landmark after the optic disc?
Macula (fovea)
What does the Mary Lyon X inactivation hypothesis have to say about
heterozygous carriers of red or green colorblindness (both of which are on the
X)?
It should not be a matter of dominant vs recessive, but her retina must be a
mosaic
What is it that allows the sodium channel in the rod outer segment close?
Removal of cGMP by phosphodiesterase
In the visual projection, where is the first place where inputs from both eyes
can connect to the same cell?
Not until the cortex
What is lost making people with age related macular degeneration (AMD) blind?
Cone (foveal) vision
Return to Syllabus
Return to Stark Home Page
this page was last revised 8/3/09