C2006/F2402 '09 -- Outline for Lecture 19
(c)2009 Deborah Mowshowitz . Last updated 04/07/2009 02:09 PM.  

Handouts (Not on web): 19A = Smooth & Skeletal muscle structure; 19B = Skeletal muscle contraction; 19C = Muscle AP's;  19D = Heart Structure & Blood Circulation.

I. Smooth Muscle -- How does it Contract?

    A. Important properties -- Can integrate multiple signals and maintain "tone" over wide range of length with economical use of ATP. (See last lecture for more details)

     B. Review of Structure

1. Arrangement of actin/myosin bundles -- see handout 16C, 19A or this picture.

2. Intermediate filaments -- connect dense bodies & help hold bundles in place. (Dense body = same function as Z line in skeletal muscle.)

3. 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.

4. Structure of nerve/muscle synapse -- not same as in skeletal muscle. Compare handouts 19A (nerve/smooth muscle)  and 14B (nerve/skeletal muscle). 

• Neurons have multiple varicosities (points of contact with smooth muscle -- contain vesicles of neurotransmitter).
• Smooth muscle has no complex structure at synapse (no motor endplate). One smooth muscle cell (or group of cells) can get input from both PS and S. See Sadava 47.8, expt. 2.

    C. How Ca⁺⁺ Triggers Contraction.

1. Requires Calmodulin.

a. Calmodulin = major Ca⁺⁺ binding protein.

b. Many affects of Ca⁺⁺ are modulated by calmodulin. Ca⁺⁺ binds calmodulin, and then complex binds to target proteins, activating (or inhibiting) target proteins. (See Becker 14-14 [14-13].)

c. For role of calmodulin in smooth muscle contraction, see Becker fig. 16-24 & handout 19A.

2. Activates myosin. See 119A.

a. Calmodulin-Ca⁺⁺ complex forms

b. Calmodulin--Ca⁺⁺ complex binds to and activates a kinase (MLCK)

c. Kinase phosphorylates and activates myosin (so it can bind actin).

d. How do 2nd messengers influence this?

• IP3 increases cytosolic Ca⁺⁺.
• The cAMP pathway (through PKA) phosphorylates myosin kinase (MLCK). Phosphorylation of  MLCK inhibits binding of MLCK to Calmodulin.

3. Bridge Cycle. Myosin binds actin, and bridge cycle follows; details not completely known.

4. Where Ca⁺⁺ comes from:

a. Some Ca⁺⁺ comes from outside of cell, through Ca⁺⁺ channels in the plasma membrane.

b. Some Ca⁺⁺ is released by the ER.

c. Proportion of Ca⁺⁺ from outside and proportion from ER varies. Usually, most is from the outside.

Note: Voltage gated Ca⁺⁺ channels, not voltage gated Na⁺ channels, are responsible for the rise in the spike of the AP in smooth muscle. Therefore Ca⁺⁺ enters during the spike.

II. Skeletal Muscle -- How does it Contract? -- see animations listed at start of previous lecture, and handouts 19A & B. 

    A. Details of skeletal muscle structure & overview of how filaments slide-- see handout 19A or Sadava fig. 47.1 & 2 (47.3) or Becker Ch. 16, figures 16-10 to 16-15 for structure; fig. 16-16 for sliding model.

   B. Role of Ca⁺⁺, troponin and tropomyosin (see handout 19 B or Sadava fig 47.3 (47.4) or Becker 16-19.

1. Structure: Tropomyosin and troponin are part of the thin filaments

2. Tropomyosin role -- blocks myosin binding sites on actin

3. Ca⁺⁺ binds to troponin (not tropomyosin)

4. Effect of Ca⁺⁺ binding -- binding to troponin → movement of tropomyosin, exposing actin binding sites, so bridge cycle can start

    C. Bridge Cycle -- How ATP is used to power sliding of thick and thin filaments -- steps (1 to 4) & states (A to E) match those on handout 19B. See also Becker 16-18; Sadava fig 47.6 (this includes role of Ca⁺⁺ as well as ATP). Cycle can start anywhere, but description below assumes you start with state B on handout and carry out step 1 first. Role of Ca⁺⁺ is omitted in this go round.

1. ADP-myosin binds to actin -- P_i released ( converting state B → state C)

2. Power stroke -- myosin, actin slide relative to one another. ADP released at end or after power stroke (converting state C →  state D).

3. ATP binds to myosin -- Myosin detaches from actin (converting state D →  state E = state A)

4. ATP is split -- form high energy form of myosin (ADP & P_i remain bound) -- Converting state A/E to state B.

5. Continue with step 1. Note ATP must continue to be split to maintain cross bridges and therefore tension in fiber.

6. How bridge cycle is blocked/regulated

a. In absence of Ca⁺⁺, bridge cycle is blocked at step 1 above.

b. In absence of ATP (& presence of Ca⁺⁺), cycle blocked at step 3 (rigor mortis).

Try problem 9-1, parts A, B & E, 9-11, and 9-12.

   D. Summary of Role of ATP & ATPase

1. ATP must be split to run bridge cycle in all types of muscle. In smooth muscle, ATP is needed, in addition, to activate myosin using myosin kinase (MLCK).

2. Myosin (not actin) has the ATPase activity. The catalytic site that splits ATP during the bridge cycle is in the myosin head (myosin is the 'motor' molecule).

3. Speed of cycle. The bridge cycle is similar in smooth and skeletal muscle, but speed of cycle is much slower in smooth muscle. In smooth muscle, cross bridges stay intact longer.

    E. How does motor neuron trigger contraction in skeletal muscle? See Becker fig. 16-21  or Sadava 47.5

1. Presynaptic side: AP comes down motor neuron → releases transmitter (AcCh)

2. Postsynaptic side -- events at membrane/motor endplate:

a. AcCh binds to nicotinic receptors on motor endplate (See handout 14B for structure of endplate & synapse)

b. Depolarization of muscle membrane = EPP (end plate potential)

c. One AP in neuron → One EPP = sufficient depolarization to trigger AP in membrane of muscle fiber (One EPSP is not sufficient to trigger an AP in postsynaptic neuron.)

3. T tubules & SR -- Where does the Ca⁺⁺ come from?

a. AP in muscle plasma membrane (sarcolemma) spreads to T tubules. For a picture, click here.
For another picture that shows another aspect, click here.

b. AP in T tubule → Ca⁺⁺ release from SR. Changes in membrane potential in T tubule → change in shape of protein in T tubule membrane → opening of channels in SR (SR = sarcoplasmic reticulum = ER of muscle cell)  → release of stored Ca⁺⁺

(Coupling is probably mechanical between a voltage sensitive protein in the T tubule membrane and the channel in the SR membrane. The coupling system is similar, but not exactly the same, in smooth & cardiac muscle. Details of Excitation-Contraction coupling in muscle are in Lecture 22 of '05 if you are interested.)

Try problems 9-2 & 9-4.

    F. Compare & Contrast: How Ca⁺⁺ triggers contraction in Smooth Muscle vs Skeletal

1. Role of Ca⁺⁺

a. Affects state of thick or thin filaments?

b. What protein binds Ca⁺⁺ ?

2. Where Ca⁺⁺ comes from: ER or outside cell?

    G. Twitches and Contractions

1. What's a twitch = 1 contraction = response to one EPP; measured by force exerted by muscle fiber when it contracts.

2. Twitches are summed. See Sadava fig. 47.9 (47.7) and handout 19-C.

a. Twitch lasts longer than muscle membrane AP

b. Second AP can trigger twitch before first is over →  more contraction (shortening)

c. Tetanus: Multiple AP's can → fully contracted muscle that stays contracted = tetanus (requires continual splitting of ATP to maintain contraction).

3. Speed. Speed of twitch depends on multiple factors.  The following information is included FYI only. There are two main types of fibers, fast twitch and slow twitch. (See tables below.)

a. Fast/slow vs glycolytic/oxidative: Usually fast twitch fibers are glycolytic; contract quickly but fatigue easily; Slow twitch fibers are oxidative -- contract slowly but fatigue more slowly.  Some muscle fibers are fast but oxidative.

b. Effect of Exercise:  Exercise changes enzyme content and therefore glycolytic/oxidative differences, but not slow vs. fast or # fibers. (Does change fiber size.) Slow and fast are innervated differently, and that can't be changed.

    H. Types of skeletal muscle fibers and contractions -- See Sadava fig. 47.10 (47.8). This section (H) is included FYI only. If you are interested, see Sadava, section 47.2;

1. Muscle can be fast twitch or slow

2. Muscle can be oxidative or glycolytic

III. Heart Structure/function

    A. Two Types of cardiac muscle cells

1. Contractile cells

a. Bridge cycle etc. much like skeletal.

b. FYI: Similar to oxidative/slow twitch skeletal (see above) -- low fatigue rate but very oxygen dependent.

c. Cells are coupled electrically (gap junctions at intercalated disks)

d. Special features of AP in membrane (see handout 19-C)

(1). 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 & figs. 47.9 (47.7)  & 49.7 (47.8) of Sadava)

(2). 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 & 49.7 (49.8) in Sadava.)

e. Role of Pacemakers.

(1). Trigger for contraction is signal from pacemaker cells of heart, not from AP of nerve.

(2). Contractile cells do not have pacemaker activity.

2. Pacemaker cells -- see handout 19-C (fig. 14-16) or Sadava fig. 49.5 (49.6).

a. Have pacemaker activity -- Fire spontaneously

b. Mechanism of pacemaker activity: Depolarize slowly to threshold → pacemaker potential → AP when reaches threshold.

c. Set pace of heart beat -- Autonomic neurons release transmitters that slow or speed up pace.

d. Channels -- pacemaker potential (spontaneous depolarization) results because of opening/closing of ion channels; to start,  more Na⁺ goes in and/or less K⁺ leaks out. (Authorities differ in the details.)

e. Special Features of AP -- AP (spike in potential) in pacemaker cells & in smooth muscle cells is largely due to inrush of Ca⁺⁺ not  Na⁺.  (see fig. 14-6, panel (c) on handout 19-C). When cells depolarize to threshold, voltage gated Ca⁺⁺ channels, not voltage gated  Na⁺ channels, are opened.

3. What accounts for differences in function between the two types of cardiac cells? Have different channels. Look at handouts to see how differences in electrical properties correlate with differences in channels, ion flows, etc.

See Problems 11-1 & 11-2.

    B. Structure of heart --  Where are the contractile and pacemaker cells? See handout 19D, Sadava Fig. 49.2 (49.3).

1. Orientation: Note all pictures of heart show person facing you, so "right" 1/2 of heart is on left of picture.

2. Structure: "Subway diagram" on top of handout shows what is connected to what, but no real anatomy.

3. Anatomy: Pictures in middle of handout show approximations of actual structures.

    C. Position, function of pacemaker cells (nodes), bundle of His, Purkinje fibers  -- see Sadava fig. 49.6 (49.7) & handout 19D.

1. All these cells have pacemaker activity -- make up the conduction system -- carry the AP to all parts of the heart. Note these cells are muscle, not nerve.

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. 

    D. Overall view of circulation  -- 17D, bottom and Sadava p. 1045 (945).

1. There are 2 loops of circulation -- to lungs (pulmonary) and to body (systemic) -- see picture on bottom of handout. Different blood vessels go in parallel to various parts of body.

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.

Note:  Gas exchange was discussed briefly in lecture 3 (see the section on the anion exchanger.) A more detailed discussion of Gas Exchange is in Lecture 23 of '05.  The details of this topic will not be covered in lecture and you are not responsible for them. A link is included if you are curious or studying for MCATs.

See problems 11-3 to 11-5.

Next time: Wrap up of heart & circulation (if necessary); then homeostasis -- How does a multicellular organism maintain a (relatively) constant internal environment?