C2006/F2402 '08 -- Outline for Lecture 16 --  (c) 2008 D. Mowshowitz  -- Lecture updated 03/31/08

Useful Web Sites & Animations

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

Handouts  16C PNS  Others: (not on web): 16A (muscle structure) & 16B (cross bridge cycle); A & B are very similar to pictures in your texts. Extra copies of all handouts are available in boxes on 7th floor Mudd.

I. How Nervous System is Organized, cont.

    A. Simple circuits  -- see handout 15B, bottom or Sadava fig. 46.3

1. Review of Last time: One synapse, 2 neurons -- monosynaptic circuit -- how sensory neuron signals an effector.

2. Circuit with multiple synapses -- how antagonistic muscles are controlled. (Signal to skeletal muscle is always +; a signal (+) means contract; no signal means relax.)

3. Role of brain -- adds up/down (as vs. in/out) component

4. FYI: Where is all this located? see Sadava fig. 46.3; will not be discussed in class.

    B. How is NS organized overall? See handout 15 B, Becker 13-1 (9-1) or Sadava fig. 46.1

1. CNS = brain + spinal cord

2. PNS -- Names of Divisons

a. Afferent vs Efferent.

(1) Afferent = carrying info into the CNS
(2) Efferent
= carrying info away from the CNS

b. Efferent subdivided into: Somatic vs autonomic

(1) Somatic = controls skeletal muscle
(2). Autonomic = controls everything else

c. Autonomic subdivided into: Parasympathetic (PS) vs Sympathetic (S)

Try problem 8-8, part I.

    C. How do PS and S co-operate? (See Sadava fig. 46.10) What do they do?

1. What do they innervate?

a. Many organs innervated by both

b. Some organs innervated (stimulated) by only one

(1). liver, sweat glands -- S only

(2). tears -- PS only

2. What results does stimulation produce?

a. Not always S excites; PS inhibits. Ex: salivation -- S inhibits; PS excites

b. Usually:

(1). S response needed in a crisis

(2). PS response needed in relaxed state.

c. Examples:

(1). S heart rate up; liver releases glucose; bladder relaxes (to hold more);

(2). PS heart rate down, digestion, salivation up.

    D. General Set up of wiring of efferent PNS -- see handout 16C

1. First neuron -- same in Somatic and Autonomic

a. Location -- body in CNS

b. Neurotransmitter -- releases AcCh (Acetyl choline)

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

d. Effect -- effect of transmitter on next cell is always excitatory

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 (norepinephrine)

c. Receptor (on effector)

(1). AcCh (cholinergic) receptor is muscarinic

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

(3). Effect of transmitter can be excitatory or inhibitor.

d. Adrenal medulla second neuron. Medulla composed of many neurons with short axons. Release neurotransmitter (mostly E = epinephrine) 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.

    E. Major receptors in the PNS -- Reference & summary -- See table in last lecture.

II. Muscle Overview

    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 [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.

5. Use ATP to power contraction

    B. Three main types -- smooth, cardiac and skeletal (See handout 16 A or Sadava fig 47.7 (47.1) 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 (and anything on smooth or skeletal muscle not covered) will be covered next time.

     C. Some Major Differences

1. Structure -- See handout 16A.

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

b. Striated vs. not.

2. What controls contraction?

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++ from ER. (ER called sarcoplasmic reticulum or SR in muscle.)

b. Smooth Muscle

(1). Innervated (not enervated) by autonomic neurons. See 16C. 

(2). Contraction influenced by hormones as well as autonomic neurotransmitters

(3). 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.

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

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

(6). Ca++ to trigger contraction comes from outside cell &/or ER.

c. Cardiac Muscle

(1). Pacemaker controls contraction.

(2). What is pacemaker activity? Cell membrane gradually depolarizes without any external stimulus. (No stable RMP.) See handout 16A.

(3). Depolarization caused by opening/closing of ion channels.

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

(5). Autonomic NS can affect pacemaker. Transmitters can effect opening/closing of channels and thereby change timing of pacemaker. (More details next time.)

(6). All cardiac muscle and some smooth muscle has pacemaker activity.

Not all individual cardiac muscle cells or all individual smooth muscle cells have pacemaker activity. Only a few specialized cells act as pacemakers. 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.

3. 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?

4. 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.

III. 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 16A 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 16C. 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.

    C. How Ca++ Triggers Contraction.

1. Requires Calmodulin. Calmodulin = major Ca++ binding protein. Many affects of Ca++ modulated by calmodulin. Ca++ binds calmodulin, and then complex binds to target proteins, activating (or inhibiting) target proteins. See Becker fig. 16-24 (23-24) & handout 16C.

2. Activates myosin. See 16C.

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.

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

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

    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.

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

Next Time: wrap up of smooth muscle if needed, & a little on cardiac muscle; then regulation of cell cycle.