C2006/F2402 '11 -- Outline for Lecture 21
(c)2011 Deborah Mowshowitz . Last updated 04/22/2011 04:26 PM.  

Handouts  21-A -- Smooth & Skeletal muscle structure -- on Courseworks
                21-B -- Skeletal muscle bridge cycle
                21-C -- Action Potentials & Pacemaker potentials -- on Courseworks

Useful Web Sites & Animations (See also the web-sites page.)

• Actin-myosin crossbridge.  Watch the myosin head swivel, attaching and detaching from actin. From San Diego State University.
• Muscle structure and contraction

There are many other good sites with animations. Please let me know if you find any that are especially helpful.

I. Muscle Overview, cont.  -- See handout 20C, bottom

    A. Common Features

1. Have actin (MF) and myosin

2. Actin and myosin slide past each other; neither shortens. (For skeletal muscle, see Becker fig. 16-16.)

3. Electrically excitable -- Stimulus usually generates an AP (in muscle membrane) which then triggers contraction; some smooth muscles respond w/o generating an AP.

4. Use Ca⁺⁺ to stimulate contraction  --  Stimulus usually causes a rise in cytoplasmic (cytosolic) Ca⁺⁺ in muscle → contraction. But details of where Ca⁺⁺ comes from, what triggers its release, and how it acts, differ in different muscles.

5. Use hydrolysis of ATP to power contraction.

6. Bridge Cycle.  All muscles achieve contraction (shortening of muscle) by a bridge cycle. Details of cycle differ.

    B. Three main types -- smooth, cardiac and skeletal (See handout 20C or Sadava Chap. 48 (fig 47.7) or Becker Chap. 16. Compare Becker figs. 16-10, 16-22 & 16-23.

The major features of smooth and skeletal muscle are outlined separately below, but actual lecture may skip back and forth.

   C. Control of bridge cycle

    1. Common features: All use Ca⁺⁺, actin, myosin, & ATP to run bridge cycle , but details differ.

    2. Differences to Keep Track Of: Main differences between striated and smooth muscle are summarized here for reference; are discussed in detail below.

a. What protein binds Ca⁺⁺? Calmodulin or troponin/tropomyosin complex?

b. What protein is altered to allow contraction -- actin or myosin?

c. When actin or myosin is altered, what is nature of change? Change in conformation &/or in state of phosphorylation?

d. Where does the Ca⁺⁺ come from? Primarily extracellular or ER?

e. Is ATP needed to maintain contraction?

     D. Some Major Differences

1. Structure -- See handout 20C

a. Cells Fused?

    (1). No -- Smooth muscle -- individual, unfused cells.

    (a). Single Unit smooth muscle -- the cells are connected by gap junctions and contract as a unit -- are electrically coupled. (See handout 21A.)

    (b). Multi unit smooth muscle -- the cells are not coupled electrically; cells are stimulated and contract as multiple individual units.

    (2) Fused at ends -- cardiac

    (3) Fused, multinucleate  -- skeletal

b. Striated vs. not. How are actin/myosin fibrils arranged? Bundles or sarcomeres?

c. Structure of nerve/muscle synapse. See handout 18, or text, for diagram of nerve-skeletal muscle synapse. Structure is different  in smooth muscle; See handout 21A.

2. What controls contraction?

a. Skeletal Muscle

(1). Innervated (not enervated) by somatic system (motor neurons)

(2). Signal (for contraction) is always excitatory.

    (a). Skeletal muscle does get hormonal stimulation (has receptors for hormones), but hormones do not affect contraction.

    (b). Nerve that synapses on skeletal muscle can be inhibited -- in that case, muscle gets no signal and does not contract. Nerve to muscle can get an inhibitory signal, but muscle itself cannot.

(3). Receptors: Neurotransmitters at nerve/muscle synapse use nicotinic cholinergic receptors (direct -- ionotropic).

(4). Source of Ca⁺⁺: Stimulus (from motor neuron) generates an AP in the muscle membrane, which causes release of Ca⁺⁺ from ER. (ER called sarcoplasmic reticulum or SR in muscle.)

b. Smooth Muscle

(1). Innervated (not enervated) by autonomic neurons. See handout 21A.  

(2). Stimulus can be excitatory or inhibitory.

(a). Examples in previous lectures: epinephrine can cause smooth muscle contraction (through IP3 in arterioles) or relaxation (through cAMP in bronchi). See Handout 19B.

(b). Response depends on type of receptors on smooth muscle.

(c). Stimulus can be from NT or hormone. Contraction influenced by hormones as well as autonomic neurotransmitters

(3). Receptors: Neurotransmitters at nerve/muscle synapse use muscarinic cholinergic receptors or adrenergic receptors (indirect -- metabotropic).

(4). Source of Ca⁺⁺: Ca⁺⁺ to trigger contraction comes from outside cell &/or ER.

(5). Stimulus doesn't always generate an AP in muscle membrane.

(6). Pacemakers? Pacemaker activity, not external stimulus, controls contraction in some smooth muscles. (See below.)

(7). Has latch state. Unlike striated muscle, can remain contracted longer without input of ATP.

c. Cardiac Muscle

(1). Contraction controlled by pacemaker cells. (Remember the Loewi experiment -- isolated hearts beat without any innervation.)

(2). Pacemakers can be speeded up or slowed down by

(a). Hormones

(b). NTs of autonomic NS.

II. Pacemakers

1. No stable RMP -- have pacemaker potential instead.

2. Cell gradually depolarizes, reaches threshold, and fires an AP.

1. All cardiac muscle and some smooth muscle have cells with pacemaker activity.

2. Only some cells in each muscle, not every single cell, have pacemaker activity.
Not all individual cardiac muscle cells or all individual smooth muscle cells (in single unit muscle) have pacemaker activity. Only a few specialized cells act as pacemakers.

1. Hormones

2. NTs of autonomic NS

    E. How do Pacemakers work?

1. Depolarization caused by opening/closing of ion 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.)

2. It's a Cycle: When depolarization reaches threshold, cell fires an AP. Membrane then hyperpolarizes, and depolarization starts again.

3. How do hormones and/or neurotransmitters affect pacemakers? Signal molecules can effect opening/closing of channels and thereby alter time required to reach threshold.

4. Channels involved -- different from usual ones needed to generate RMP, AP etc. If you are curious about the details, see physiology texts.

Question: What opens the channels responsible for the pacemaker potential? Are the channels  ligand gated? Voltage gated? Mechanically gated?

At this point, if you haven't done it yet, it helps to start making a table that summarizes all the similarities and differences between the 3 types of muscle. Fill it in as you go -- add to it as you find out more about the structure and function of the different types.

III. Smooth Muscle -- How does it Contract?

    A. Important properties -- Can integrate multiple signals and maintain "tone"  (state of tension/contraction) over wide range of length with economical use of ATP.

     B. Important Features of Structure

1. Arrangement of actin/myosin bundles -- see handout 21A 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 (reminder)

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 18 (nerve/skeletal muscle). 

• Presynaptic Side: Neurons have multiple varicosities (points of contact with smooth muscle -- contain vesicles of neurotransmitter).
• Postsynaptic Side: 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 fig. 48.8 (47.8, expt. 2).

    C. How Ca⁺⁺ Triggers Contraction.

1. Requires Calmodulin.

a. What is Calmodulin? It's the major Ca⁺⁺ binding protein.

b. Role of Calmodulin: Many effects 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, or Sadava 48.9 (not in 7th ed) & handout 21A.

2. Activates myosin. See 21A (& 19B).

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⁺⁺, causing contraction.
• The cAMP pathway (through PKA) phosphorylates myosin kinase (MLCK). Phosphorylation of  MLCK inhibits binding of MLCK to Calmodulin, causing relaxation.
• See below for more details on roles of MLCK & 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 (FYI): 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.

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

    A. Overview of skeletal muscle structure & role of actin & myosin -- see handout 21A or Sadava fig. 48.1 & 2 (47.1 & 2) or Becker Ch. 16, figures 16-10 to 16-15 for structure; fig. 16-16 for sliding model.

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

2. Power stroke -- myosin, actin slide relative to one another. Myosin straightens up, pushing actin to left -- converting state C →  state D. (ADP released) .

3.  Myosin detaches from actin  -- converting state D →  state E = state A. (Requires binding of ATP).

4. High energy or 'cocked' form of myosin formed -- Converting state A/E to state B. (Requires splitting of ATP.)

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. See below.

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.

  C. Summary of Role of ATP & ATPase

1. How ATP is used to power sliding of thick and thin filaments in striated muscle.

a. P_i released at step 1.

b. ADP released at step 2 -- during or after power stroke.

c. ATP bound at step 3.

c. ATP split (hydrolyzed) at step 4 -- ADP & P_i remain bound.

2. 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).

3. 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).

4. 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.

   D. Role of Ca⁺⁺, troponin and tropomyosin (see handout 21 B or Sadava fig 48.3 (47.3) or Becker 16-19.

1. Structure: Tropomyosin and troponin are part of the thin filaments (bound to F-actin).

2. Regulation: Ca⁺⁺ regulates conformation of tropomyosin/tropinin complex and binding of myosin to actin.

a. Low Ca⁺⁺ -- Tropomyosin/tropin complex covers myosin binding sites on actin. (Step 1 on handout is blocked.)

b. High Ca⁺⁺ -- Troponin/tropomyosin complex changes conformation, uncovering the myosin binding sites. Step 1 can proceed.

3. Details (fyi)

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

b. Troponin role -- Ca⁺⁺ binds to troponin (not tropomyosin)

c. Effect of Ca⁺⁺ binding -- binding to troponin → movement of tropomyosin, exposing binding sites on actin , so myosin can bind and bridge cycle can start

    E. How does motor neuron trigger contraction in skeletal muscle? See Becker fig. 16-21  or Sadava 48.5 (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 18 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 (or complex) 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. 48.10 (47.9)

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 for those interested in exercise physiology. 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: 

    (1). 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.

    (2). Exercise increases mostly size of fibers, not number. A limited number of muscle stem cells exist, so minor repairs are possible. Major repairs and big increases in fiber number are not possible.

    H. Types of skeletal muscle fibers and contractions -- See Sadava fig. 48.11 (47.10). This section (H) is included FYI only. If you are interested, see Sadava, section 48.2 (47.2).

1. Muscle can be fast twitch or slow

2. Muscle can be oxidative or glycolytic

V. Heart Muscle Contraction.

    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 cardiac muscle membrane

(1). AP lasts much longer (as long as contraction).   See handout 21C or Sadava fig. 50.7 (49.7).

(2). Cause of long AP. Prolonged AP (long depolarized phase) is due to delay in opening of slow voltage gated K⁺ gates and to opening of Ca⁺⁺ channels. See handout or Sadava fig. 50.7 (49.7).

(3). Result of long AP -- Extended refractory period prevents heart muscle tentany. Each contraction ends before next AP arrives. Next contraction cannot occur until previous contraction is over. (Compare to skeletal muscle.)

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 21-C or Sadava fig. 50.5 (49.5), and details above. 

a. Have pacemaker activity -- Fire spontaneously

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

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

3. What accounts for differences in function between the two types of cardiac cells? Differences in AP between skeletal and cardiac muscle? Have different channels. If you need more details, consult physio or neuro texts 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.  See texts or web for pictures if you are curious. Note that all pictures of heart show person facing you, so 'right' 1/2 of heart is on left of picture.

    C. (FYI) Position, function of pacemaker cells (nodes), bundle of His, Purkinje fibers  -- see Sadava fig. 50.6 (49.6)

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  --  Sadava p. 1050 (1049) -- will be discussed next time if we don't get to it.

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 (and sections B & C above) 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.