C2006/F2402 '08 -- Outline for Lecture 17
(c)2008 Deborah
Mowshowitz . Last updated 04/01/2008 01:24 PM.  

Handouts (Not on web): 17A = Muscle AP's; 17B = Heart Structure & Blood Circulation.

I. Skeletal Muscle Contraction  -- see animations listed at start of previous lecture, and handouts 16A & B. 

    A. Details of skeletal muscle structure & overview of how filaments slide-- see handout 16A or Sadava fig. 47.1 & 2 (47.3) or Becker Ch. 16, fig. 10-15 (Chap 23, same figures).

    B. 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 16B. See also Becker 16-18 (23-18); 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.

   C. 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.

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.

    D. How does Ca++ trigger contraction (on postsynaptic side) in skeletal muscle? See Becker fig. 16-23 & 21 (23-20 & 21) or Sadava 47.5

1. Overall: Ca++ is released from SR (ER).

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

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

a. AcCh binds to nicotinic receptors on motor endplate

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.)

4. T tubules & SR

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.)

5. How does Ca++ act in the muscle?

a. Affects state of thin filaments.

b. Ca++ binds to troponin tropomyosin moves exposes binding sites on actin. Actin can now bind to myosin, and bridge cycle can start.

Try problems 9-2 & 9-4.

  E. Compare & Contrast: How Ca++ triggers contraction in Smooth Muscle

1. Role of Ca++:

a. Affects state of thick filaments

b. Ca++ binds to calmodulin Ca++/calmodulin complex actives myosin kinase phosphorylation and activation of myosin. Myosin can now bind to actin and start bridge cycle. (Details in last lecture.)

2. 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.

3. How Ca++ enters the cytosol (soluble part of cytoplasm)

a. From ECF -- Can enter through ligand gated &/or voltage gated channels: Neurotransmitters, hormones etc. open Ca++ channels in plasma membrane either directly or indirectly. (Either APs or graded potentials can open voltage gated channels.).  Details depend on type of muscle.

b. From ER. GPCR's generate second messengers (usually IP3) that trigger release of Ca++ from ER.

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.

   D. 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 17-A.

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.

    E. Types of skeletal muscle fibers and contractions -- See Sadava fig. 47.10 (47.8). This section (E) is included FYI only.

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
Overal 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

II. 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 17-A)

(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 17A (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. (See notes of last time.)

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

d. Special Features of AP -- AP (spike in potential) in pacemaker cells is largely due to inrush of Ca++ not  Na+.  (see fig. 14-6, panel (c) on handout 17A). 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 17B, 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.

    B. Position, function of pacemaker cells (nodes), bundle of His, Purkinje fibers  -- see Sadava fig. 49.6 (49.7) & handout 17B.

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. 

    C. Overall view of circulation  -- 17BA, 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.

III. Signaling, cont.; Significance of RTK's (Receptor Tyrosine Kinases)

    A.  Review: What are the basic types of receptors?

1.  Intracellular Receptors.  Internal (intracellular) receptors for lipid soluble ligands (steroids & TH).

2. Cell Surface Receptors. For water soluble ligands.

a. GPLRs (or GPCRs) -- Cell surface (transmembrane) receptors linked to G proteins (also called G Protein Coupled Receptors or  GPCRs)

(1). Usually generate second messengers

(2). Two major pathways involving second messengers (See handout 12A & below.)

            (a). G protein Adenyl Cyclase (AC) cAMP

            (b). G protein (different one) Phospholipase C (PLC) IP3 & DAG

b. Channels -- some transmembrane receptors are ion channels. The most famous example is the nicotinic acetyl choline receptor -- the receptor involved in nerve-muscle signaling, and in the first synapse in the autonomic division of the PNS. 

c. RTKs -- Cell surface (transmembrane) receptors that are  -- or are linked to -- tyrosine kinases.

   B. Details for DAG/IP3/Ca++ pathway. See handout 12A & Becker figs. 14-9 & 14-10 (10-8 & 10-9) or Sadava 15.13 (15.11)

1. How IP3 and DAG are generated.

a. Activated G protein binds to phospholipase C (PLC)

b. PLC cleaves PIP2 in membrane PIP3 (soluble, in cytoplasm; also known as InsP3) and DAG ( remains in membrane). For structure see handout 12A and Becker fig. 14-9 (10-8).

c. Other inositol derivatives are involved in signaling -- this is a current hot subject of investigation.

2. Role of IP3/Ca++

a. IP3 opens Ca++ channels in the ER, raising Ca++ in cytoplasm. (Becker fig. 14-11 (10-10) for IP3 effect; fig 10-11 for overall Ca++ regulation.)

b. Ca++ acts alone or binds to protein named calmodulin; complex (calmodulin-Ca++) or Ca++ alone alters activity of many proteins. (See Becker fig. 14-13 (10-12)  for pictures of calmodulin.)

c.  Ca++ affects many processes -- sometimes called "3rd messenger." Changes in [Ca++] can trigger exocytosis (& secretion) or muscle contraction & big changes in Ca++ levels are involved in egg fertilization (see Becker fig.14-14 (10-13) or Sadava  15.14 (15.12) for some nice pictures). 

3. Role of DAG

a. DAG (in membrane) activates protein kinase C (= PKC, not to be confused with PLC).

b. "PKC" is a family of related enzymes involved in many different processes -- act by phosphorylating other proteins. If you are interested, see Becker or advanced texts for details. Some PKC's require Ca++.  PKC and PKA have different target proteins.

Try problems 6-5, 6-10 & 6-16.

    C. What is special about RTKs? RTK's are representative of a different type of cell surface receptor involved in signaling. Different features from GPCR's. For example:

a.  Structure different from GPCR's.

b. Signal is water soluble, but often activates TF. Signal on outside of cell binds to receptor, and activation of proteins, often TF's, happens inside.

c. Activation (of primary target proteins) occurs without a G protein or second messenger. How can the binding of a ligand on the outside of the cell activate proteins inside without a second messenger? What's the path of 'signal transduction?' More details next time.

    D. Role in Cancer & Regulation of the Cell Cycle

1. RTK's control the normal cell cycle

2. Many cancer cells have mutations affecting RTK's or their targets (proteins normally activated by RTK's).

3. Two major types of mutations responsible -- RTK targets are always 'on' as a result of one of the following:

a. Stuck accelerator (stimulation uncontrolled) -- RTK, its ligands, or targets are either overproduced or stuck in active form

b. Brake failure (inhibition fails) -- Inhibitors of RTK or its targets are missing or inactive.

Next time: How do normal RTK's work? What goes wrong in cancer cells?