C2006/F2402 '04 Outline for Lecture 21(c) 2004 Deborah Mowshowitz
Last Update: 04/16/2004 09:29 AM . See additions & corrections to II.4.B on pacemakers.
Handouts: 21A (Heart Action Potentials); 21B (Heart Structure & Circulation); 21C (Gas Exchange -- to be covered next time); 21D -- Smooth Muscle Structure. Handouts are not on web; extras are in boxes outside 700 Mudd.
Some Nice Web Links on the Heart
I. Skeletal Muscle, cont. Fast Twitch vs. Slow Twitch -- see previous lecture.
II. Smooth muscle
A. Ca++ triggers contraction
1. Role of Ca++: State of thick filaments, not state of thin, are affected by Ca++.
2. Where Ca++ comes from: Most Ca++ comes from outside of cell, not SR. AP opens voltage gated Ca++ chanels and Ca++ comes in from extracellular fluid (ECF). More on this below.
1. Smooth muscle contains no troponin (does have tropomyosin, but doesn't block actin-myosin binding sites)
2. Arrangement of actin/myosin bundles -- see handout 21D, bottom.
C. Calmodulin controls contraction/Ca++ response (instead of troponin). See Becker fig. 23-24 & Handout 21D, middle..
1. Calmodulin-Ca++ complex forms
2. Calmodulin--Ca++ complex binds to and activates a kinase (MLCK)
3. Kinase phosphorylates and activates myosin (so it can bind actin)
D. Actin accessibility may be regulated by other factors, but not Ca++
E. Cross bridge Cycle -- Can maintain stable cross bridges for a long time without breaking ATP (because of slow bridge cycle -- slow ATPase and slower Ca++ pump. Still need one ATP used per cross bridge made/broken.)
F. Speed -- contraction is slower than with skeletal, because:
1. A component requires phosphorylation before bridge cycle can begin
2. ATPase of myosin slower; get slower contraction (slower bridge cycle) but less fatigue
G. Trigger for contraction -- innervation
1. Autonomic system and/or hormones, not somatic (as for skeletal).
a. Stimulus can be excitatory or inhibitory. Hormones and autonomic neurotransmitters from postganglionic neurons affect channels & pumps indirectly using 2nd messengers. (Compare to situation with nerve/muscle synapse.)
b. Stimulus can generate an action potential (which in turn affects Ca++ channels) or act through a second messenger to affect Ca++ levels (w/o going through an AP). Examples in previous lectures: epinephrine can cause smooth muscle contraction (through IP3) or relaxation (through cAMP and Ca++ pump). Response depends on receptors on smooth muscle.
c. Some smooth muscles have pacemaker cells that generate an AP spontaneously. Autonomic and/or hormonal stimulation modulate effects of internal signals from pacemakers.
2. Structure of nerve/muscle synapse is different -- neurons have multiple varicosities (points of contact with smooth muscle -- contain vesicles of neurotransmitter), and muscle has no complex structure at synapse (no motor endplate). One autonomic neuron can stimulate multiple smooth muscle cells &/or multiple points on a single muscle cell. See handout 21D, top. One neuron can get input from both PS and S.
Try problem 9-1, parts C & D, and try answering question 9-4 for the case of smooth muscle. If we finish smooth muscle, you should be able to do all of the problems in set 9.
II. Cardiac Muscle
A. Contractile cells
1. Bridge cycle etc. much like skeletal. See below for details of Ca++ role.
2. Similar to oxidative/slow twitch skeletal -- low fatigue rate but very oxygen dependent,
3. Cells are coupled electrically
4. Special features of AP in membrane (see handout 21-A)
a. AP lasts much longer (as long as contraction) so tetany is impossible. Each contraction ends before next AP arrives. (see fig. 14-5 on handout & 47.11 (44.11) of Purves)
b. Prolonged AP (long depolarized phase) is due to delay in opening slow voltage gated K+ gates and opening of Ca++ channels. (see fig. 14-14 on handout)
5. Role of Pacemakers. Trigger for contraction is signal from pacemaker cells of heart, not from AP of nerve. (Autonomic neurons do release transmitters that slow or speed up contractions; see below.)
B. Pacemaker cells -- found in heart and some smooth muscle -- see handout 21-A (fig. 14-16) or Purves 49.7 (46.8).
1. Set pace of heart beat
2. Fire spontaneously
3. Depolarize slowly to threshold --> pacemaker potential ---> AP when reaches threshold
4. Depolarization caused by flow of Na+ into the cell. Na+ goes through a Na+/K+ channel similar to one ---> EPSP. This channel = If channel on handout 21A. Na+ leaks in slowly, depolarizing the cell to threshold. The If channels are called "funny" channels because they open when the cell is hyperpolarized, not when it is depolarized. (Ca++ movement is also involved in the late phases of the pacemaker potential; see advanced texts if you are interested. See below for role of K+.)
Note: The ion flows & channels that generate the pacemaker potential are quite complex. The slow depolarization during the pacemaker potential is caused by the closing of K+ leak channels out of the cell, in addition to the opening of If channels that allow Na+ in. Since the K+ flow out (through leak channels) is reduced, the slight Na+ leak in (through the If channels) depolarizes the cell. If the K+ leak channels remain open, they can counterbalance the effects of Na+ leakage. Transmitters and/or hormones can alter the state of the leak channels &/or the If channels.
5. Role of Autonomic innervation. S/PS release transmitters --> open/shut K+ leak channels and/or the If channels --> faster or slower depolarization = steeper or flatter pacemaker potential ---> fire sooner or later --> faster or lower heartbeat. (see Purves 46.8)
6. AP in pacemaker cells largely due to voltage gated Ca++ channels, not voltage gated Na+ channels (see fig. 14-6, panel (c) on handout 21A)
See Problems 11-1 & 11-2.
C. Excitation-Contraction Coupling -- how AP in muscle plasma membrane leads to cross bridge activity within the muscle.
1. What occurs in both cardiac & skeletal muscle:
a. AP in muscle membrane travels into T tubules.
b. Proteins in T tubule membrane are activated (change conformation) in response to voltage differences.
c. Activated receptors in T tubule (called DHP or dihyropyridine receptors) trigger opening of Ca++ channels in ER/SR (called ryanodine receptors). How DHP receptors open channels in ER is different between the two muscle types -- linkage is mechanical in skeletal muscle; through Ca++ release in cardiac muscle. See below.
d. Ca++ released from ER/SR.
e. Increase in cytoplasmic Ca++ triggers start of cross bridge cycle.
f. Contraction ends when Ca++ removed. (Ca++ is sent back where it came from -- Pumped back into ER or out of cell using ATP.)
2. What is different in smooth muscle
a. No T tubules.
b. DHP receptors in membrane are also (voltage gated) Ca++ channels. (Also the case in cardiac muscle; see below.)
c. Most Ca++ comes into smooth muscle cell from ECF using channels in plasma membrane.
c. Some additional Ca++ may be released from ER as described below. (By "Ca++ induced Ca release.")
d. Ca++ pumped out of cell (or back into ER) after contraction.
3. Details for cardiac muscle
a. Voltage activated proteins (DHP receptors) in membrane are Ca++ channels (as in smooth muscle)
b. DHP receptors/channels are mostly in T tubules (as in skeletal muscle.)
b. AP triggers opening of Ca++ channels in T tubule; Small amount of Ca++ from extracellular fluid (ECF) in T tubule enters cytoplasm.
c. "Ca++ induced Ca release": Small amount of Ca++ from ECF binds to receptors on surface of ER and opens Ca++ channels (ryanodine receptors) in ER/SR --> release of large amounts of Ca++ into cytoplasm. (Occurs in smooth muscle, too but amount of Ca++ release from ER not as significant.)
d. Ca++ removed by pumping it back into ER or ECF.
4. Summary of Excitation-Contraction Coupling
|Skeletal Muscle||Cardiac Muscle||Smooth Muscle|
|DHP receptors are also Ca++ channels?||No||Yes||Yes|
|Coupling of DHP receptors to ryanodine receptors/ER channels||Mechanical||Through Ca++||Through Ca++|
|Major source of cytoplasmic Ca++||ER/SR||ER & ECF||ECF|
|Ca+ induced Ca++ release from ryanodine receptors/ER channels?||No||Yes||Yes (but most Ca++ is from ECF)|
Researchers uptown recently discovered a drug that blocks leaky ryanodine receptor channels and prevents heart failure. See the press release or the full article in Science pdf version or html version.
III. Heart Structure & Function (See handout 21B). Where are the contractile and pacemaker cells?
A. Structure of heart -- Purves Fig. 49.4 (46.5) -- note all pictures show person facing you, so "right" 1/2 of heart is on left of picture. "Subway diagrams" on top and bottom show what is connected to what, and how overall blood flow goes, but no real anatomy. Pictures in middle show approximations of actual structures.
B. Position, function of pacemaker cells (nodes), bundle of His, Purkinje fibers -- see Purves fig. 49.8 (46.9) & handout middle right.
1. All these cells have pacemaker activity -- make up the conduction system -- carry the AP to all parts of the heart.
2. SA node usually in charge. SA node has the fastest firing rhythm -- normally controls heart beat. Fires first.
3. Role of AP in SA node. Causes atria to contract, pushing blood into ventricles. Causes AV node to fire after a short delay
4. AP in AV node spreads to bundle of His and Purkinje fibers
5. Bundle of His etc. causes ventricles to contract, from bottom up, pushing blood out top of heart.
See Problems 11--3, 11-4, & 11-6.
C. Overall view of circulation -- see handout 21B and Purves p. 870 (fig. 46.4 (f))
1. There are 2 loops of circulation -- to lungs (pulmonary) and to body (systemic) -- see picture on bottom. Different blood vessels go in parallel to various parts of body. (Helps to compare all pictures on 21B to understand the structure of heart and circulation.)
2. Arteries go away from the heart; don't necessarily carry oxygenated blood
3. Structure: Arteries and veins, arterioles and venules are surrounded by smooth muscle; capillaries are not.
4. Cardiac cycle -- systole & diastole
a. Systole -- ventricles contract, blood pumped out to system
b. Diastole -- ventricles relax; fill with blood
c. Note: the terms systole (contraction) and diastole (relaxation) can be used to refer to the state of the ventricles or to the state of the atria. In common usage, the terms always refer to the state of the ventricles.
See problem 11-5. Gas Exchange Next Time -- Bring Handout 21C.
IV. Gas Exchange -- how do you get O2 to cells and CO2 to lungs? See Gas Exchange handout (21C) & Purves 48.18 (45.17).
A. Exchange (of oxygen, carbon dioxide & other nutrients and waste) at capillaries. (For structures see Purves fig.48-12 ( 45-12) or handout 21C.
1. materials in alveoli exchange with materials in pulmonary capillaries
2. materials in cells exchange with materials in systemic capillaries
3. capillaries have large surface area and slow flow of blood, promoting exchange
B. How is O2 carried?
1. Hemoglobin (Hb) binds & traps O2 in red blood cell (RBC) at lungs (See handout 21C, panel B)
2. Hb releases O2 in tissues (See handout 21C, panel D)
3. Important properties of Hb that enable it to function properly -- see curve of % saturation of Hb vs pO2. Purves fig. 48.14 (45.14). Note sigmoid shape of curve. pO2 = partial pressure of O2 = measure of concentration of free (not bound) O2 = measure of concentration of O2 dissolved in blood or liquid part of tissue.
a. Plateau means Hb always saturated with O2 in lungs
b. Curve is steep in range of pO2 found in tissues -- so releases O2 as needed.
c. Sigmoid curve indicates allosteric enzyme; binding of O2 is co-operative. O2 affinity shifts with amount of O2 already bound/lost. Promotes tendency to empty of fill up completely (with O2).
d. Affinity of Hb for O2 can change due to genetic [urves fig. 48.15 (45-15)] or environmental differences [Purves fig. 48-16 (45-16)].
(1). lower affinity shifts curve to right; higher affinity shifts curve to left (takes less O2 to fill Hb up).
(2). Ligands bound to Hb can change affinity and shift curve. For example, DPG (2,3 diphosphoglycerate) -- found only in RBC -- shifts curve to right ---> optimal affinity for job
(3). Changing amino acid sequence slightly can shift curve right or left. Example: HbF (fetal Hb) has higher affinity; suits its job. See Purves fig. 48.15 (45-15)
(4). Conditions in tissues (Low pH, high CO2) shift curve to right, allowing Hb to unload O2 where needed, and H+ and CO2 to bind to deoxygenated Hb. (Reverse happens in lungs.) See Purves fig. 48-16 (45-16).
C. How is CO2 carried? See handout 21C panels A & C or Purves fig. 48.17 (45.17)
1. What happens in tissues? (panel C on 21-C)
a. CO2 from metabolism enters RBC
b. Inside RBC, carbonic anhydrase (one of fastest enzymes known; turn over # of 6 X 105/sec) converts CO2 to carbonic acid. Traps CO2.
c. Carbonic acid disassociates into bicarbonate and H+
d. Anion exchanger (band 3 protein) switches bicarb (in cell) for Cl- in blood.
e. Some H+ binds to Hb (deoxygenated)
2. What happens in lungs? (Panel A on 21-C)
a. Process described above reverses -- bicarb. reenters cell, made back into CO2, etc.
b. CO2 released to air (low CO2 in alveloli/air pull CO2 off by Le Chatelier's principle; higher CO2 conc. in blood than in alveoli)
c. O2 helps drive off CO2 and H+ from Hb. (Additional push factor.)
Next Time: Gas Exchange; How is salt & water balance maintained?