C2006/F2402 '14 -- Outline for Lecture 22
(c) 2014 Deborah Mowshowitz . Last updated 04/20/2014 09:30 AM.  

Handouts  22-A -- Smooth muscle innervation & contraction, and Skeletal muscle structure
                22-B -- Skeletal muscle bridge cycle & 3 types of muscle

22A & 22B are on Courseworks, because they contain copyrighted material. You can pick up paper copies on the 7th floor of Mudd after the lecture. You can get pictures of all the structures mentioned using Google Images.

You also need Handout 21C & D

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 other videos by this author at

http://www.physioviva.com/animation_list.html and at http://www.youtube.com/user/llkeeley?feature=mhee

Please let me know if you find any of these (or any other animations on these topics) especially helpful. Also let me know if any of these links do NOT work.

For all the biology related videos of Khan Academy, go to https://www.khanacademy.org/science/biology -- there are videos on muscle contraction and many related matters.

For additional pictures (& an explanation) of the material discussed below, go to

I. How does a nerve or hormonal signal produce an effect, cont?  This is material that was accidentally omitted from topic III of the notes for Lecture #21. It provides backup to the diagrams on handout 21B. This material (Topic I) was covered last time and will not be reviewed in #22.

    A.  General solution -- signal triggers an effect in a target tissue (an effector) -- muscle contracts, gland secretes, etc. Some examples of how this works were discussed in Lecture #21. Below are more details.

    B. The Problem --  One signal molecule (hormone, transmitter, etc.) can produce different effects on different target tissues such as different smooth muscles or skeletal muscle vs. smooth muscle. 

   C. Two Basic Methods -- See Handout 21B.  This topic was included in Lecture #21, in III-C, but this is a more complete version.

1.  Using the Same Receptor & same signaling pathway, but different Target Proteins (or genes)

        a. Previous examples:

(1). Insulin effects on skeletal muscle vs liver -- Insulin activates (&/or inhibits) different target proteins in the two different tissues

(2). Estrogen effects on uterine tissue vs breast tissue -- Estrogen receptor/TF affects transcription of different genes in the two different tissues (because of different proteins that affect the action of the TF differently in the two cell types).

b. A new example: epinephrine (epi) effects on two types of muscle

(1). In skeletal muscle: epinephrine causes glycogen breakdown (as explained previously).

(2). In smooth muscle of lung: epinephrine causes muscle relaxation.

c. Why does this make sense?

(1). Epinephrine (also called adrenaline) is produced in response to stress.

(2). In response to stress,  need to "mobilize" glucose -- release it from storage so it can be broken down to provide energy. Therefore need to increase glycogen breakdown (and decrease glycogen synthesis) in muscle (& liver).

(3). In response to stress, need to breathe more deeply. Therefore need smooth muscle around tubes that carry air (bronchioles) to relax.

d. How is this possible?  Same receptors, same 2nd messenger (cAMP) are used.

e. The solution: Different target proteins. PKA is activated in both skeletal and smooth muscle. However the target proteins available to be phosphorylated are different in the two tissues. Therefore different proteins are phosphorylated and activated (or inactivated) in the two different tissue types.

(1). In skeletal muscle -- PKA phosphorylates (& activates) the enzyme phosphorylase kinase,  which in turn phosphorylates (& activates) the enzyme that breaks down glycogen to release glucose.  See texts for more details. (Becker, fig. 14-25 or Sadava fig. 7.18 (7.20)

(2). In smooth muscle surrounding the bronchioles -- PKA phosphorylates a protein (MLCK) needed for contraction, inactivating it. Therefore contraction cannot occur.

  2. Using different receptors & second messengers in different cell types 

(See Becker fig. 14-24 (14-23). An example -- effects of epinephrine (adrenaline) on smooth muscle. Some smooth muscles relax, and some contract in response to epinephrine. In this case, different receptors & 2nd messengers are involved. How does this work? See below.

Try problem 6-11.

  D. Example of Using Different Second Messengers (& Different Receptors). Details of examples on handout 21B.

1. The phenomenon:

a. Epinephrine (secreted in response to stress) has different effects on different smooth muscles:

           (1).  On some smooth muscles, epi → contraction
 
           (2). On other smooth muscles, epi →  relaxation (as above)

b. How does this make sense?

(1). In peripheral circulation -- smooth muscles around blood vessels (arterioles) contract, diverting blood from peripheral circulation to essential internal organs

(2). In lungs -- smooth muscles around tubes carrying air (bronchioles) relax, so lungs can expand more and you can breathe more deeply.

2. How Ca⁺⁺ fits in:

a. Ca⁺⁺ stimulates muscle contraction.

b. To give contraction: Epinephrine binds to receptors on some smooth muscles  (ex: around arterioles) → Ca⁺⁺ released from ER → intracellular Ca⁺⁺ up → stimulates contraction. 

c. To give relaxation: Epinephrine binds to receptors on some smooth muscles (ex: around bronchioles)  → phosphorylates protein needed for response to Ca⁺⁺,  preventing response.

3. Role of receptors

a. Two basic types of epinephrine  receptors -- called alpha and beta adrenergic receptors (adrenergic = for adrenaline). The two types are distinguished (primarily) by their relative affinities for epinephrine (adrenaline) and norepinephrine (noradrenaline).

b. Some types of smooth muscle have mostly one type of receptors; some the other. (See table below and table in previous lecture for details of receptor properties.)

c. Two types of receptors activate different G proteins and generate different second messengers. (Details next time.)

(1). Beta receptors → G protein of one type (G_s)→ activates enzyme (Adenyl cyclase)  → second messenger (cAMP) → PKA

(2). Alpha 1  receptors → different G protein (G_p) → activate different enzyme (phospholipase C or PLC) → different second messenger (IP3) → binds to receptors on ER membrane → opens Ca⁺⁺channels in ER → Ca⁺⁺ release from ER → contraction

4. How does this all work to allow appropriate response  to stress (epinephrine)?

a. Beta type receptors. Beta receptors are found in lung tissue in smooth muscle surrounding bronchioles.
Stress (pop quiz, lion in street, etc.)→ epinephrine → muscles relax → bronchioles dilate →  deeper breathing → more oxygen → energy to cope with stress. 

b. Alpha type receptors. Alpha receptors are found in smooth muscle surrounding blood vessels of peripheral circulation.
Stress → epinephrine → muscles contract → constrict peripheral circulation → direct blood to essential organs for responding to stress (heart, lungs, skeletal muscle).

To review effects of different receptors, try problems 6-21 & 6-22.

5. Medical Uses of all this.

Epinephrine can be used during an asthmatic attack to relax bronchi and ease breathing. Overuse of this type of broncho-dilator eases breathing temporarily but masks underlying problem (inflammation of lung tissue) and can have additional serious long term effects (from overstimulation of heart which also has beta receptors). Heart and lungs have slightly different types of beta receptors, so drugs (agonists) have been developed that stimulate one and not the other (unlike epinephrine).  Many drugs are either agonists or antagonists of signaling molecules such as hormones, transmitters, etc.

Try Problem 6-8 & 6-9 if not yet. (To review agonists & antagonists.)

6. Summary of epinephrine effects on smooth muscle (in lung vs peripheral circulation). See also handout 21B.

Note: There are more than two types of epinephrine receptors on smooth muscle cells, so epinephrine may affect smooth muscle in other tissues in other ways.  (There are subtypes of alpha and subtypes of beta.)

* Details of how PLC generates IP3 are in texts and on handout 21A.
** Not all alpha receptors use IP3.

II. How Nervous System is Organized (Handouts 21C & 21D)

    A. How is NS organized overall? See handout 21C top, or Sadava fig. 47.1.

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.

    B. How do PS and S co-operate? See Sadava fig. 47.9 (47.10).  What do they do?

1. What do they innervate?

a. Many organs innervated by both

b. Some organs innervated (stimulated) by only one

(1). sweat glands -- S only

(2). tear glands -- 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. ("para makes you pause")

c. Examples:

(1). S → heart rate up; liver releases glucose; bladder relaxes (to hold more) -- urination down; digestion down. 

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

    C. General Set up of wiring of efferent PNS -- see handout 21D

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 (direct)

d. Effect -- effect of transmitter on next cell is always excitatory (Why? What's the mechanism?)

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

a. Location -- Body in ganglion (outside CNS).

• PS ganglion -- Proximal to target

• S ganglion -- close to Spinal cord; first neuron is Short.

b. Neurotransmitter

(1). Parasympathetic -- releases AcCh

(2). Sympathetic -- usually releases NE (norepinephrine)

c. Receptor (on effector) -- indirect (metabotropic)

(1). AcCh (cholinergic) receptor is muscarinic

(2). NE (adrenergic) receptor can be alpha or beta (see below & table in previous lectures) -- 2nd messenger varies

(3). Effect of transmitter on effector -- response of effector can be excitatory or inhibitory.

Examples: Smooth muscle may contract or relax; heart may beat faster or slower. (Response depends on type of G protein activated by receptor.)

d. Adrenal medulla

        (1). Medulla ≡ ganglion -- but neurons have short axons. (Usual 'neuron #2' has long axon.)

        (2). Release neurotransmitter (mostly E = epinephrine) into blood from end of short axons (within medulla).

        (3). Role of E -- 'NT' goes into blood, so E acts as neuroendocrine instead of neurotransmitter.

Try problem 8-8 part J.

    E. Major receptors in the PNS --For details, see summary table in Lecture #20.

1. Acetyl Choline Receptors -- two main types, nicotinic (direct/ionotropic) & muscarinic (indirect/metabotropic)

2. Adrenergic Receptors -- two main types -- alpha & beta. Both indirect (metabotropic)

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.)

3. Electrically excitable  

a. Stimulus usually generates an AP (in muscle membrane) which then triggers contraction

b. Some smooth muscles respond (contract) w/o generating an AP.

4. Use Ca⁺⁺ to stimulate contraction  

a. Stimulus usually causes a rise in cytoplasmic (cytosolic) Ca⁺⁺ in muscle → contraction.

b. Details differ: 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 -- How the 'sliding' works

a. All muscles achieve contraction (shortening of muscle -- sliding of actin relative to myosin) by a bridge cycle = cycle of formation and breaking of connections between actin and myosin  

b. All use Ca⁺⁺, actin, myosin, & ATP to run bridge cycle, but details differ.

    B. Three main types -- smooth, cardiac and skeletal (See handout 22B for pictures or Sadava Chap. 48 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. When doing the problems, consult the handouts on the bridge cycle and smooth muscle contraction mechanism as needed.

     C. Some Major Differences

1. Structure -- See handout 22B

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.

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

(2) Functionally fused -- cardiac -- uninucleate but tightly connected at ends 

(3) Fused, multinucleate  -- skeletal

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

c. Structure of nerve/muscle synapse.

(1) Somatic Innervation  -- See  texts for diagram of nerve-skeletal muscle synapse. Similar to nerve-nerve synapse on handout 20A, but post-synaptic side is more elaborate.

(2). Autonomic Innervation -- Synapse structure is different -- NT is released from varicosities, not from special nerve ending. See handout 22A.

• 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.

2. What controls contraction?

a. Skeletal Muscle

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

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

(3). 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.)

(4). 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.

    (c). How are antagonistic muscles controlled? See handout 21C, and 'simple circuits' below.

b. Smooth Muscle

(1). Innervated (not enervated) by autonomic neurons. See handout 22A.  

(2). Stimulus can be excitatory or inhibitory.

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

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

(c). Examples

    i.  Using hormones: epinephrine can cause smooth muscle contraction (through IP3 in arterioles) or relaxation (through cAMP in bronchi). See Handout 21B.

    ii. Using NTs: In smooth muscle of gut, NE causes excitation (depolarization); AcCh causes relaxation (hyperpolarization). See Sadava fig. 48.8 for effects of NT input on membrane potential in smooth muscle (from GI tract).

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

(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. If no AP involved, can trigger release of Ca⁺⁺ (leading to contraction) by one of the following:

    (a). Graded changes in membrane potential (due to external stimulus or pacemaker)

    (b). Activation of a GPCR by a NT or hormone

(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. See Sadava  fig. 50.6 (50.5)

    D. Simple circuits  -- see handout 21C, bottom or Sadava fig. 47.3 (9th ed only). Integrating sensors, effectors, and IC (CNS).

1. One synapse, 2 neurons -- monosynaptic circuit -- how sensory neuron signals an effector.

2. Circuit with multiple synapses -- how antagonistic muscles are controlled. For example, when stretch is detected in a muscle, that muscle contracts and the antagonistic muscle relaxes.

a. Signal to skeletal muscle is always +; a signal (+) means contract; no signal means relax.

b. Signal to neuron (that controls muscle = innervates it) can be excitatory or inhibitory. 

c. What makes the (antagonistic) skeletal muscle relax?

• Relaxation occurs because the antagonistic muscle gets no signal to contract.

• The muscle does not get an inhibitory signal -- it just doesn't get an excitatory signal.

d. Who gets an inhibitory signal? The motor neuron that innervates (goes in to) the antagonistic muscle gets an inhibitory signal, not the muscle itself. The motor neuron is inhibited and does NOT fire an AP, so the muscle is not triggered to contract.

e. Terminology -- the term 'innervate' means ' to synapse on' and 'to control'. It does not mean enervate (decrease the vigor of). Innervate and enervate are completely different in meaning.

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

4. FYI: Where is all this located? see Sadava fig. 47.3 (9th ed); will not be discussed in class.

III. 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.

    D. 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 or Sadava fig. 50.5 (10th ed only)

Question: What triggers opening of the channels responsible for the pacemaker potential? Are the channels ligand gated? Voltage gated? Mechanically gated?
 

IV. 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 22A 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 22A (nerve/smooth muscle)  and 20A (nerve/nerve --similar to nerve/skel. 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 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.)

c. For role of calmodulin in smooth muscle contraction, see Becker fig. 16-24, or Sadava 48.9 & handout 22A.

2. Activates myosin. See 22A

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? See 18B.

• 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.

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.

Try Problem 9-6, 9-13 & 9-14.

V. Skeletal Muscle -- How does it Contract? -- see animations listed at start of lecture, and handouts 22A & B. 

    A. Overview of skeletal muscle structure & role of actin & myosin -- see handout 22A or Sadava fig. 48.1 & 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).

7. Summary of 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.

Try problem 9-1,  9-11, and 9-12. Consult the bridge cycle handout if needed.

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. Role of Ca⁺⁺ & protein complex (troponin and tropomyosin) See Sadava fig 48.3 or Becker 16-19.

1. Overall

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

b. High Ca⁺⁺ --  Ca⁺⁺ binding causes protein complex to change conformation,  uncovering the myosin binding sites. Step 1 can proceed.

2.  Protein complex details (FYI)

a. Protein Complex =  Tropomyosin & troponin.

b. Location -- Tropomyosin and troponin are part of the thin filaments (bound to F-actin). One molecule of tropomyosin covers several molecules of G-actin.

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

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

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

    F. How does motor neuron trigger contraction in skeletal muscle? See Becker fig. 16-21  or Sadava 48.5

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 texts for detailed 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.)

d. AP in muscle fiber triggers release of Ca⁺⁺ → contraction of muscle.

3. T tubules & SR -- Where does the Ca⁺⁺ come from?

a. AP in muscle plasma membrane (sarcolemma) spreads to T tubules. (T tubule = extension of membrane deep into the muscle fiber.)

b. AP in T tubule membrane → 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. Consult the bridge cycle handout if needed.

    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 in skeletal muscle are summed. See Sadava fig. 48.10

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. Twitches/contractions in cardiac muscle are not summed

a. Special features of AP in cardiac muscle membrane

(1). AP lasts much longer (as long as contraction). See Sadava fig. 50.8 (50.7).

(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. 50.8 (50.7).

(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.)

b. 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. Only selected cells -- those in nodes -- have pacemaker activity. See Sadava fig. 50.7

(3). What controls pace of heart beat?  Autonomic neurons release transmitters that slow or speed up pace set by pacemakers. See Sadava fig. 50.5

c. Cells are coupled electrically (gap junctions at intercalated disks)

4. 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.

5. Speed. (FYI!) 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 for more details if you are interested.)

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.

VI. How does Contraction Occur? 

Some important differences to keep track of are summarized here for reference;  details about striated and smooth muscle contraction are above.

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

b. What protein is altered to allow contraction -- actin or myosin? What is affected, thick or thin filaments?

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 significant 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.

  The remainder of the material is included FYI in case you are interested, or studying for MCAT or GRE.

  A. Details of Types of skeletal muscle fibers and contractions -- See Sadava fig. 48.11. If you are interested, see Sadava, section 48.2.

1. Muscle can be fast twitch or slow

2. Muscle can be oxidative or glycolytic

VIII. Heart Muscle Contraction -- more details.

    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.

2. Pacemaker cells -- see Sadava fig. 50.5 and details above. 

See Problems 11-1 & 11-2.

    B. Structure of Heart.  See texts or web for pictures if you are curious. In real pictures and diagrams, the 2 halves of heart are joined, not separate, unlike diagram on handout 18A. Note that all pictures of heart show person facing you, so 'right' 1/2 of heart is on left of picture.

    C. Position, function of pacemaker cells (nodes), bundle of His, Purkinje fibers  -- see Sadava fig. 50.7

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. Review of Overall view of circulation -- (See handout 18A and Sadava, chapter 50)

1. There are 2 loops of circulation -- to lungs (pulmonary) and to body (systemic) -- see picture on bottom of handout and Sadava p. 1030 (1050).

2. How reach tissues?  Different blood vessels go in parallel to various parts of body. See handout 18A.

3. Arteries go away from the heart; don't necessarily carry oxygenated blood

4. Structure of blood vessels: Arteries and veins, arterioles and venules are surrounded by smooth muscle; capillaries are not. Structures are shown in Sadava figs. 50.13 & 50.14.

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 and Sadava Chapter 49.  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.