C2006/F2402 '10 -- Outline for Lecture 19
(c)2010 Deborah
Mowshowitz . Last updated 04/04/2010 12:04 PM.  

Handouts (Not on web): 19A = Smooth & Skeletal muscle structure
    19B = Skeletal muscle contraction;
    19C = Muscle AP's

I. Comparison of 3 Types of Muscles, cont.

    A. What controls contraction?

1. Skeletal Muscle

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

b. Signal is always excitatory.

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

d. Role of AP & 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.)

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

2. Smooth Muscle

a. Innervated  by autonomic neurons. See handouts. 

b. Contraction influenced by hormones as well as autonomic neurotransmitters

c. Stimulus can be excitatory or inhibitory.

Examples in previous lectures: epinephrine can cause smooth muscle contraction (through IP3) or relaxation (through cAMP). Response depends on receptors on smooth muscle.

d. Stimulus doesn't always generate an AP in muscle membrane. When there is an AP, the spike is caused by inrush of Ca++, not Na+. (Same as with pacemakers; See handout 19C.)

e. Role of Pacemaker -- pacemaker activity, not external stimulus, controls contraction in some smooth muscles. See below.

f. Source of Ca++ -- Ca++ to trigger contraction comes from outside cell &/or ER.

g. Has latch state; unlike striated muscle. Can remain contracted longer without input of ATP.

3. Cardiac Muscle & Pacemakers

a. Pacemaker & autonomic NS control contraction of heart. (As shown in the Loewi experiment.)

    (1).  Isolated heart beats without any innervation.

    (2). Transmitters of autonomic NS affect pacemaker.

b. What is pacemaker activity? Cell membrane gradually depolarizes without any external stimulus. See handout 19C.

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

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

c. All cardiac muscle and some smooth muscle has pacemaker activity.

    (1). 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.

    (2).  Role of pacemaker cells: All cardiac muscle and some smooth muscle will contract without nerve input because these muscles contain pacemaker cells. The pacemaker cells fire APs simultaneously, and this stimulates the other cells, the contractile cells (that do not have pacemaker potentials), to contract.

    B. 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. Role of hormones and/or Neurotransmitters -- 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.

a. Role of If channels (see handout 19C).

  • If channels = Na+ channels that open at low voltage, when cell is hyperpolarized.
  • Why the name?  If stands for 'funny channels'.

    'Normal' voltage gated Na+ channels open to generate an AP when cell is depolarized.
     'Funny' Na+ channels open to generate an AP when cell is hyperpolarized.

b. Role of voltage gated Ca++ channels  

  • When pacemaker cells depolarize to threshold, voltage gated Ca++ channels, not voltage gated  Na+ channels, are opened to generate AP.
  • Spike is largely due to inrush of Ca++ not  Na+.  (see fig. 14-6, panel (c) on handout 19-C).
  • AP in smooth muscle cells is due to Ca++, not Na+, as with pacemakers.

Q: Why will Na+ or Ca++ work to generate an AP, but not K+?

    C. Control of bridge cycle

    1. Common features: All use Ca++, actin, myosin, & ATP to run bridge cycle (see notes of last time), 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?

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?

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.

II. 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. (See last lecture for more details & comparison to cardiac & skeletal muscle.)

     B. Important Features of Structure

1. Arrangement of actin/myosin bundles -- see handout 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 (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 16B (nerve/skeletal muscle). 

    C. How Ca++ Triggers Contraction.

1. Requires Calmodulin.

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

b. Role of Calmodulin: 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 19A.

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: 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. (See 19C.)

III. 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 -- Pi 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 & Pi 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 16B 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 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. 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

  Fast Twitch Slow Twitch
ATPase of Myosin Higher Lower
Speed of Bridge Cycle Faster Slower
Reach max. tension (after EPP) Rel. quickly Rel. slowly
Size/ max. possible tension Usually larger Usually smaller
Overall Properties of Muscle "flash in the pan" "slow but steady"
Used for quicker response,
bursts of activity (sprinters)
slower response,
sustained activity (long distance runners)

2. Muscle can be oxidative or glycolytic

  Glycolytic Oxidative
Color paler ("white meat") Red color due to myoglobin to store oxygen ("red meat")
# of capillaries to deliver oxygen Rel. low Relatively high
# of mitochondria for oxidative metabolism Rel. low Relatively high
Need for oxygen Low High. Need more oxygen but less glucose -- "Oxygen dependent" but energy metabolism is more efficient
Ease of Fatigue  Rel. quickly relatively slowly -- Does not accumulate lactic acid
Glycolytic enzymes Higher Lower

IV. 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 (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). Cause of long AP. Prolonged AP (long depolarized phase) is due to delay in opening slow voltage gated K+ gates and to 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), and details above in I-B.

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? 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. Wrap up of heart & circulation -- will do in lecture 23.

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.

Next time: Introduction to Immunology. In lecture 23 we will finish immunology, and do wrap up of heart & circulation. Then on to homeostasis -- How does a multicellular organism maintain a (relatively) constant internal environment?