C2006/F2402 '07 Outline for Lecture 23 --  (c) 2007 D. Mowshowitz  -- Lecture updated 04/25/07

Useful Web Sites & Animations

Handouts (not on web): 23A (muscle structure) & 23B (cross bridge cycle); 23 C (stress response, smooth muscle, & pacemaker potentials).  A & B are very similar to pictures in your texts. Extra copies are available in boxes on 7th floor Mudd.

I. Peripheral Nervous System -- Wrap up of receptors, wiring, etc. See end of last lecture (IV-D to F) & Handout 22A (top).

    A. General Set up of wiring of efferent PNS -- see handout 22A (This is the same as IV-D of last lecture.)

1. First neuron -- same in Somatic and Autonomic.

a. Location -- body in CNS

b. Neurotransmitter -- releases AcCh

c. Receptor -- AcCh receptor (on effector/next neuron) is nicotinic

2. Second neuron (post ganglionic) -- found in autonomic only

a. Location -- Body in ganglion

b. Neurotransmitter

(1). Parasympathetic -- releases AcCh

(2). Sympathetic -- usually releases NE

c. Receptor (on effector)

(1). AcCh (cholinergic) receptor is muscarinic;

(2). NE (adrenergic) receptor can be alpha or beta (see table in last lecture.)

d. Adrenal medulla second neuron. Medulla composed of many neurons with short axons. Release neurotransmitter (mostly E) from end of short axons (within medulla). E goes into blood, so E acts as neuroendocrine instead of neurotransmitter.

Try problem 8-8 part J.

    B. Receptors in the PNS -- Reference & summary -- See IV-E in last lecture.

    C. PS vs S factors to compare and contrast -- See IV-F in last lecture.

. Stress response -- How do hormones (cortisol & epinephrine) and nerves act together? Example: response to stress.  (Handout 23C, top.)

    A. Phase one -- Nerve (Sympathetic) activity stimulates target organs (that are not glands) Direct response of heart, liver, lungs, etc.

    B. Phase two -- Nerve (Sympathetic activity) activation of glands

1. Stimulate pancreas glucagon released stimulated; insulin release inhibited secretion of glucagon additional stimulation of some target organs

2. Stimulate adrenal medulla release of epinephrine stimulation of same targets as sympathetic nerve activity & some additional targets -- hormones can reach where nerves can't go.

    C. Phase three -- stimulate HT/AP axis to produce cortisol

 HT in brain releases CRH AP releases ACTH adrenal cortex produces cortisol target organs stimulation of breakdown of fats & protein for energy (sparing glucose for brain); inhibition of immune system.

Note that each additional phase is slower but involves additional degrees of amplification due to second messengers, transcription, etc.

III. Muscle Overview

    A. Three main types -- smooth, cardiac and skeletal (See handout 23 A or Purves 47.1 (47.5) or Becker Chap. 16 (23). Compare Becker figs. 16-10, 16-22 & 16-23 (23-10, 23-22, 23-23).

The major features of smooth and skeletal muscle are outlined separately below, but actual lecture may skip back and forth. Details of cardiac muscle will be covered next time.

    B. 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 [23-16].)

3. Electrically excitable -- Usually generate an AP in response to stimulation; some smooth muscles respond w/o generating an AP.

4. Use Ca++ to stimulate contraction  -- But details of where Ca++ comes from, and how it acts, differ; see below.

    C. Some Major Differences

1. Structure -- See handout 23C.

a. Cells Fused? Single cells (smooth) vs fused at ends (cardiac) vs fused, multinucleate (skeletal) --

b. Striated vs. not.

2. Pacemaker activity or not?  (cardiac always does; some smooth muscle does). See handout 23C. What is pacemaker activity?

a. Pacemaker Potential: Cell membrane gradually depolarizes without any external stimulus. (No stable RMP.) Depolarization = pacemaker potential.

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

c. Channels involved: depolarization caused by opening of cation channels (for Na+/K+ or for Ca++ ) or closing  of K+ channels .

d. Autonomic NS effects -- can effect opening/closing of channels and thereby change timing of pacemaker.

 (1). Example (in heart): S/PS release transmitters open/shut K+ channels, Ca++ channels and/or the Na+/K+ channels   faster or slower depolarization  = steeper or flatter pacemaker potential   pacemaker cells fire AP sooner or later   faster or slower heartbeat. (see Purves 49.6 (49.7))

(2). Other effects: 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.)

3. What controls contraction? (If there is no pacemaker)

a. Skeletal Muscle

(1). Innervated by somatic system

(2). Signal is always excitatory.

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

(4). Stimulus generates an AP in the muscle membrane, which causes release of Ca++.

b. Smooth Muscle -- see Handout 23C

(1). Innervated (not enervated) by autonomic neurons & affected by hormones.

(2). Stimulus can be excitatory or inhibitory.

(a). Hormones and autonomic neurotransmitters from postganglionic neurons affect channels, pumps and other proteins indirectly, using 2nd messengers. (Use indirect, metabotropic receptors.)

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

(3). Stimulus can generate an action potential (to open Ca++ channels) or act through a second messenger to affect Ca++ levels or response to Ca++ (w/o going through an AP). 

4. Control of bridge cycle -- all use Ca++, but details differ, as explained 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? Extracellular or ER?

5. Role of ATP. Is ATP needed to maintain contraction? (See below.)

At this point, 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.

IV. 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 for both.

3.  Latch state possible -- can remain contracted for prolonged period without further input of ATP.  (One ATP split per bridge cycle, but cycle is much slower than for skeletal.)

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. Structure

1. Arrangement of actin/myosin bundles -- see handout 23A 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 -- See handout 23C. Neurons have multiple varicosities (points of contact with smooth muscle -- contain vesicles of neurotransmitter), and 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.

5. Other differences from Skeletal Muscle: No T tubules, no troponin. (Does have tropomyosin, but doesn't block actin-myosin binding sites).

    C. How 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, through Ca++ channels in the plasma membrane.

b. A little Ca++ is released by the ER.

3. How Ca++ enters the cell

a. Through ligand gated channels: Neurotransmitters, hormones etc. open Ca++ channels in plasma membrane using second messengers, and Ca++ comes in from extracellular fluid (ECF). 

b. Through voltage gated channels: Some, but not all, smooth muscles, can generate an AP, and Ca++ comes in through voltage gated Ca++ channels opened during the AP and in response to it.

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. In addition, the change in voltage can open more voltage gated Ca++ channels, allowing more Ca++ in.

4. Ca++ binding protein: Calmodulin, not troponin, controls response to Ca++.  See Becker fig. 16-24 (23-24) & handout 23C.

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 increase cytosolic Ca++; the cAMP pathway (through PKA) phosphorylates myosin kinase (MLCK). Phosphorylation of  MLCK inhibits binding to Calmodulin.

V. Skeletal Muscle Contraction  -- see animations listed at start of lecture.

    A. Details of skeletal muscle structure & overview of how filaments slide-- see handout 23A or Purves fig. 47.3 (47.7) 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 23B. See also Becker 16-18 (23-18); Purves 47.6 (47.10 -- 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 (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.

    C. Role of Ca++, troponin and tropomyosin (see handout 23B or Purves 47.4 (47.8) or Becker 16-19 (23-19)

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 go

5. 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. Where does Ca++ come from? How is it released? See Becker fig. 16-23 & 21 (23-20 & 21) or Purves 47.5 (47.9)

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

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

3. Post synaptic 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 the 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.)

Try problems 9-2 to 9-4.

   E. 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 Purves 47.7 (47.11)

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).

    F. Types of skeletal muscle fibers and contractions -- See Purves 47.8 (47.12). 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

3. Fast/slow vs glycolytic/oxidative: Usually Fast twitch fibers are glycolytic; fatigue easily etc.; Slow twitch fibers are oxidative.  Some muscle fibers are fast but oxidative.

4. Effect of Exercise -- changes enzyme content and 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.

Next Time: wrap up of smooth muscle if needed, & a little on cardiac muscle; then immune system