Physiology - 8-28-09

-------------------------------------------------------Physiology 8-2909----------------------------------------------I.

Skeletal Muscle functional anatomy i. Arranged sarcomeres gives striated characteristics to skeletal and cardiac muscle fibers b. Thin filament i. F actin ii. (G actin polymer) iii. Tropomyosin: 3 binding sites: A,B C; C is the one that moves myosin out of the way once it has combined with Ca, and allows the activated myosin to attach to a binding site for contraction iv. Troponin c. Thick filaments

II.

Smooth Muscle Functional Anatomy a. Actin b. Myosin c. Tropomyosin: d. Calmodulin: functionallhy replaces tryponin; is the regulatory protein, binds to calcium i. Major Ca binding site in cell ii. Combines with caldesmon to move tropomyosin iii. Activates kinase that phosphorylates the myosin head (at the hinge portion) e. Caldesmon: helps calmodulin interact with myosin f.

Dense bodies: takes the functional role of the Z disks i. Muscle fibers not as organized, not striated, all criss-crossed

ii. g. Sliding filament mechanism i. Z disks get closer (sarcomeres get smaller) ii. I band gets smaller iii. H zone gets smaller iv. A band doesn’t change v. vi.

vii. h. What’s causing this? i. Fact established so far: 1. Actin binding site for myosin head 2. The myosin head has a binding site for actin 3. Myosin has ATPase activity a. Release of energy cause angle of head portion of myosin molecule to rod portion to increase i.

Cross bridge cycling or Myosin cycling: i. Power stroke ii. Rigor iii. recovery

iv. 1. A 2. B: low energy, low affinity; when energy is lost, phosphate and ATP is ejected; myosin is attached, ADP and P recucled; low energy state, high affinity; made first pull; 3. C: step C: if still stimulated, ATP will rebind, will lower myosin head affinity for actin: low affinity, low energy state: myosin head has instantaneous ATP attachment; ATPase degrades ATP 4. D: high energy, high affinity; energy transferred to hinge portion so myosin head is bent back to the cocked position; goes to the next myosin attachment site; if Ca levels and ATP are still high, cycle will revolve j.

Biochemical pathway of the mechanism

i. 1. STEPS: didn’t follow this too closely 2. Hydrolysis: high energy high affinity at M-ADP; I think its generic k. Relaxation vs. contraction

i. l.

Smooth Muscle functional Anatomy (see above) i. Actin

ii. Myosin iii. Tropomyosin iv. Calmodulin v. Caldesmon vi. Dense bodes m. Smooth Muscle Crossbridge Cycling Initiation i. Primary method: 1. Calmodulim (CaM) ii. Secondary methods 1. Direct Ca induces phosphorylation of myosin head iii. Increase cytoplasmic {Ca+2) iv. Ca2+ binds to calmodulin (CaM) 1. Latch lever occurs between these volumes 2. -> 10-4 mol/l - 4 Ca 3. <- 10-7 mol/L -> 0 Ca v. CaM-4Ca 1. Activates myosin light chain kinase (MLCK) a. MLCK phosphorylates myosin head 2. Interaction of actin and myosin (via caldesmon) 3. Biochemical pathway

a.

vi. Smooth Muscle Relaxation 1. Myosin light chain Phosphorylase (MLCP) a. Not regulated b. Removes phosphate from myosin head c. Leads to relaxation when its activity dominated MLCK activity 2. Rate of cycling: a. Slower than in skeletal muscle b. Depends on Kinase/ phophatase ratio i. [Ca+2] ii. Calmodulin iii. Phosphorylation c. Can be regulated (hormones, stimulation

3. Decrease Kinase Activity a. Lower cytoplasmic [Ca+2] b. Leads to decrease in MLCK activity 4. Increase Cyclic AMP (cAMP) activity a. Membrane receptor-ligand b. Increase cAMP dependent kinase c. MLCK phosphorylated d. Decrease MLCK activity 5. Nitric Oxide ( initiates P removal, stops reaction) a. Activates guanylate cyclase i. Produces cGMP ii. Activates phospholyase iii. Phosphate removed from myosin b. A phosphodiesterase decrages cGMP to GMP i. Inhibited by slidenafil n. SUMMARY i. Contraction 1. Skeletal/ Cardiac a. Exposure of binding site (troponin – tropomyosin) 2. Smooth a. Phosphorylation of myosing (CaM-4Ca) ii. Relaxation: 1. Skeletal/ Cardiac a. Covering of binding site 2. Smooth a. Deactivation of kinase

III.

Neuron Muscle Interactions a. Skeletal muscle i. Neuromuscular junction ii. Similar to Neurons 1. RMP: -80 to -90 mV 2. AP = +30 mV 3. Duration= 1-5 sec 4. Propogation= 2-5 m/sec iii. Innervation initiate activity iv. Comparisons of AP curves 1.

b. Smooth muscle i. Multi-unit smooth muscle ii. Single-unit smooth muscle 1. Smooth Muscle Diffuse junction: a. Transmitter substance released at axon varicosities

b. Synaptic cleft wider c. Variety of Transmitter Substances i. AcH - acetylcholine ii. Nor – noreepinephrine d. Membrane receptors not localized iii. RMP not stable 1. Slow wave rhythm 2. Spike and plateau shaped AP 3. Exhibits “pacemaker” activity ( myogenicity) 4. Innervation & local factors modifies activity 5. AP due to Ca2+ influx 6. Gap junctions functionally connect cells

7. c. Cardiac muscle i. Action potential a Plateau 1. Initial part due to Na+ influx 2. Remainder due to Ca2+ influx 3. Prevents tetanization of muscle

ii. Exhibits pacemaker activity (myogenicity) iii. Intercallated disks functionally and mechanically connect cells

iv. v. Excitation- contraction Coupling 1. The process by which the excitation of the sarcolemma is transmitted to the contractile machinery within the cell 2. Involves Ca2+ ion vi. Sources of Calcium Ion 1. Skeletal Muscle a. Sarcoplasmic reticulum i. Calsequestin 2. Smooth muscle a. Extracellular fluid 3. Cardiac muscle a. Sarcoplasmic reticulum b. Extracellular fluid vii. Skeletal muscle slide

viii.

ix. Calcium entry into smooth muscle 1. “Leak channel” 2. Voltage gated Ca channels 3. Ligand gated Ca channels x. Smooth muscle Intracellular Ca release 1. A 2nd messanger 2. Cell depolarization 3. “Ca induced Ca release”

4.

xi. Cardiac Muscle E-C C 1. Anatomy: a. Like skeletal muscle i. Large diameter “T” tubule ii. Voltage gated Ca channels in sarcolemma & T tubules b. Calcium from ECF i. Sarcolemma ii. “T” tubules c. Intracellular Ca i. Sarcoplasmic reticulum 1. Ca induced Ca release

2. xii.

Calcium Exit 1. Skeletal muscle a. Ca pump in membrane of sarcoplasmic reticulum 2. Smooth muscle a. Ca pump in membrane of sarcolemma and (sarcoplasmic reticulum) b. Na co-transport 3. Cardiac muscle a. Ca pump in membrane of sarcolemma and sarcoplasmic reticulum b. Na- co-transport system