C2006/F2402 '05 Outline for Lecture 22(c) 2005 Deborah Mowshowitz
Last Update: 04/20/2005 10:19 AM .
Handouts: 22A (Heart Action Potentials); 22B (Heart Structure & Circulation); 22C (as Exchange -- to be covered next time); 22D -- Smooth Muscle Structure. Handouts are not on web; extras are in boxes outside 700 Mudd.
Some Nice Web Links on the Heart
I. Smooth muscle
A. What use is smooth muscle? What unique properties does it have?
1. Location -- much of it makes up walls of hollow organs & tubes. Maintains shape and pushes contents along.
2. Contraction speed & rate of fatigue -- relatively slow.
3. Latch state possible -- can remain contracted for prolonged period without input of ATP. (One ATP split per bridge cycle, but cycle is much slower.)
4. Length over which it contracts/stretches -- relatively long.
5. Contracts/relaxes in response to many different stimuli -- nerves, hormones, stretch, etc.
Overall: Can integrate multiple signals and maintain "tone" over wide range of length with economical use of ATP.
B. Ca++ triggers contraction
1. Role of Ca++: State of thick filaments, not state of thin, are affected by Ca++.
2. Where Ca++ comes from:
a. Most Ca++ comes from outside of cell. Neurotransmitters, hormones etc. open Ca++ channels in plasma membrane using second messengers, and Ca++ comes in from extracellular fluid (ECF). In some smooth muscles, voltage gated Ca++ channels open and generate an AP.
b. A little Ca++ is released by the ER. (See "Ca++ induced Ca release," described 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 22D, bottom.
3. Intermediate filaments -- connect dense bodies & help hold bundles in place. (Dense body = same function as Z line in skeletal muscle.)
4. No T tubules.
5. Two Types.
a. Single Unit smooth muscle -- the cells are connected by gap junctions and contract as a unit.
b. Multi unit smooth muscle -- the cells are not coupled electrically; cells are stimulated and contract individually.
D. Calmodulin controls contraction/Ca++ response (instead of troponin). See Becker fig. 23-24 & Handout 22D, 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 & hormones
1. Autonomic system and/or hormones, not somatic (as for skeletal).
a. Stimulus can be excitatory or inhibitory.
(1). Hormones and autonomic neurotransmitters from postganglionic neurons affect channels & pumps indirectly using 2nd messengers. (Compare to situation with nerve/muscle synapse.)
(2). 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.
b. Stimulus can generate an action potential (to open Ca++ channels) or act through a second messenger to affect Ca++ levels (w/o going through an AP). See examples above.
c. An external stimulus may not be needed. 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 22D, top. One smooth muscle cell (or single unit smooth muscle) 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 (gap junctions at intercalated disks)
4. Special features of AP in membrane (see handout 22-A)
a. AP lasts much longer (as long as contraction) so tetany is impossible. Each contraction ends before next AP arrives. (see fig. 14-15 on handout & 47.7 & 49.8 (47.11) 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 & 49.8 in Purves.)
5. Role of Pacemakers. Trigger for contraction is signal from pacemaker cells of heart, not from AP of nerve. (Autonomic neurons release transmitters that slow or speed up contractions; see below.)
B. Pacemaker cells -- found in heart and some smooth muscle -- see handout 22-A (fig. 14-16) or Purves 49.6 (49.7).
1. Set pace of heart beat
2. Fire spontaneously
3. Depolarize slowly to threshold --> pacemaker potential ---> AP when reaches threshold.
Overall cause of slow depolarization in heart: more Na+ and Ca++ leak in, and less K+ leaks out, gradually depolarizing the cell. The movement of ions is controlled by multiple channels -- see handouts and below.
4. Channels involved: The ion flows & channels that generate the pacemaker potential are quite complex. Here are some of the critical points; see advanced texts if you are interested in more details.
a. If channels: Na+ goes through a Na+/K+ channel similar to one ---> EPSP. This channel = If channel on handout 22A. 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.
b. K+ leak channels: 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, as explained below.
c. Ca++ channels are also involved in the late phases of the pacemaker potential.
5. Role of Autonomic innervation. S/PS release transmitters --> open/shut K+ leak channels, Ca++ channels and/or the If channels --> faster or slower depolarization = steeper or flatter pacemaker potential ---> pacemaker cells fire AP sooner or later --> faster or lower heartbeat. (see Purves 49.6 (49.7))
Note: Transmitters may also affect the threshold value needed to fire an AP and/or the maximum hyperpolarization of the pacemaker cells -- this can also affect the time between AP's. (See advanced texts if you are interested.)
6. AP (spike in potential) in pacemaker cells is largely due to inrush of Ca++ not Na+. (see fig. 14-6, panel (c) on handout 22A). When cells depolarize to threshold, voltage gated Ca++ channels, not voltage gated Na+ channels, are opened.
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 trigger opening of Ca++ channels in ER/SR. ( 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's different in cardiac muscle
a. Voltage activated proteins in membrane are Ca++ channels.
b. AP triggers opening of the 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 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.)
FYI: The voltage activated proteins in the plasma membrane referred to above are usually called DHP or dihyropyridine receptors. In smooth and cardiac muscle, the DHP receptors are also Ca++ channels. The Ca++ channels in the ER are called ryanodine receptors. (The names come from inhibitors that bind to the respective proteins.) The DHP and ryanodine receptors are coupled in all three types of muscle, but the mechanism of coupling is different.
3. What's different in smooth muscle? No T tubules; Ca++ mostly comes from outside the cell. Small amount of "Ca++ induced Ca release" from ER by same mechanism as for cardiac muscle.
III. Heart Structure & Function (See handout 22B). Where are the contractile and pacemaker cells?
A. Structure of heart -- Purves Fig. 49.3 (49.4) -- 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. 49.7 (49.8) & 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 22B and Purves p. 945 (870).
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 22B 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 ("squeeze"), 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.
IV. Gas Exchange -- how do you get O2 to cells and CO2 to lungs? See Gas Exchange handouts (22C & D) & Purves 48.14 (48.17).
A. Exchange (of oxygen, carbon dioxide & other nutrients and waste) at capillaries. (For structures see Purves fig.48-10 (48-12) or handout 22D.
1. In lungs: materials in alveoli exchange with materials in pulmonary capillaries
2. In tissues: materials in cells exchange with materials in systemic capillaries
3. Structure: capillaries have large surface area and slow flow of blood, promoting exchange
Rest of material will be covered next time.
B. How is O2 carried?
1. Hemoglobin (Hb) binds & traps O2 in red blood cell (RBC) at lungs (See handout 22C, panel B)
2. Hb releases O2 in tissues (See handout 22C, panel D)
3. Hb has many important properties that enable it to function properly; if time some will be discussed next time.
C. How is CO2 carried? See handout 22C panels A & C or Purves fig. 48.14 (48.17)
1. What happens in tissues? (panel C on 22-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+ . (This is not actually a separate step -- enzyme directly generates bicarb.)
d. Anion exchanger (band 3 protein) switches bicarb (in cell) for Cl- in blood.
e. Some CO2 and H+ binds to Hb (deoxygenated)
2. What happens in lungs? (Panel A on 22-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, cont; How is salt & water balance maintained?