Problems: Module 4

One point per item. Answers vary with the example. The rules the key grades against:

• Phasic: relaxed most of the time, contracts when needed (esophagus, intestines). Tonic: contracted most of the time, relaxes when needed (sphincters, blood vessels). (slide 4)

• Single-unit for most large-scale organs. Multi-unit where control must be precise, as in the eye. (slide 5)

• Sympathetic: contracts most vascular smooth muscle; relaxes airways, GI, urinary, and vessels in active skeletal muscle. (slide 6)

A safe worked example: airway smooth muscle, respiratory, tonic, single-unit, sympathetic relaxes it so the airways widen and more oxygen reaches the lungs.

(a) Wrong: MLCP does not touch MLCK. It dephosphorylates while MLCK phosphorylates. Competitive, not interactive. (slides 14, 16)

(b) Wrong: NE raises force through alpha-1 and alpha-2, but lowers it through beta-2. (slides 20–21)

(c) Correct as written.

(d) Wrong: only MLCK depends on Ca²⁺ (through calmodulin). MLCP works regardless of Ca²⁺.

(e) Wrong: the two work independently. When MLCK is off, MLCP keeps working, unopposed. (slides 16, 21)

One point for the verdict, one for the reason.

Phosphorylation state is directly correlated with both velocity and maximal force. High phosphorylation, fast and strong. Low phosphorylation, slow and weak. (slide 17)

Phosphorylation rises (1). Draw a new curve in the same family, starting higher and extending farther right than the 60% curve (1).

Mechanisms (0.5 + 0.5): ↑ IP₃ → more Ca²⁺ → more Ca²⁺-calmodulin → more MLCK activity. And ↑ rho kinase → less MLCP opposition.

Force of contraction increases (1). (slide 20)

cGMP raises MLCP activity → overall phosphorylation falls → net decrease in force. One point each. (slide 21)

Shifts right (1), because MLCP activity is higher from cGMP (1). A right shift means the cell is less sensitive to a given Ca²⁺ level and favors relaxation (1). (slide 22)

One point per blank plus one for attempting. Rho kinase is an enzyme, not a second messenger, so it is not in the table. (slides 12, 20–21, 40–41)

Three points per difference: 1 for the difference, 1 for why it stood out, 1 for a slide citation. Strong choices with slides: Ca²⁺ sensor (troponin C vs calmodulin, slides 13, 34); filament regulated (thin vs thick, slide 14); Ca²⁺ source (SR only vs influx plus SR, slides 12, 33); Ca²⁺ removal (SERCA alone vs SERCA, NCX, PMCA, slides 15, 35); cell shape and size (slide 44); twitch duration (slide 45); tetanus (slide 47); innervation (slides 6, 28).

(a) Wrong: Ca²⁺ enters in phase 2, the plateau. (slides 32–33)

(b) Wrong: CICR is extracellular Ca²⁺ influx triggering SR release. Channel closing is Ca²⁺-dependent inactivation, a Module 6 topic. (slides 12, 33)

(c) Wrong: calmodulin is smooth muscle only. Cardiac Ca²⁺ binds troponin C, as in skeletal muscle. (slides 13–15, 34, 36)

(d) Correct as written.

(e) Wrong: SERCA does most of the work, but NCX and PMCA also remove Ca²⁺. (slide 35)

Law (2): stretch the heart with more filling and it contracts with more force to expel that greater volume, and the reverse. Optional mechanism: stretch appears to raise Ca²⁺ sensitivity of the thin filament proteins.

Importance (2, graded generously): the heart automatically matches what it pumps out to what comes in, so blood does not back up when filling rises. (slide 37)

One point to name, one to describe, five times. Any five of: striations and sarcomeres (skeletal); troponin C as the Ca²⁺ sensor (skeletal); same thin filament proteins (skeletal); T tubules (skeletal); reliance on SR Ca²⁺ release (both); reliance on extracellular Ca²⁺ (smooth); CICR (smooth); pacemaker automaticity (smooth); autonomic modulation by extracellular ligands through GPCRs (smooth); gap junction coupling (smooth); long action potentials and twitches (smooth). (slides 27–28, 46–47)

(a) Smooth muscle’s curve lies almost flat along the bottom: its shortening velocity is tiny next to slow and fast skeletal, though maximum stress is similar.

(b) Higher phosphorylation (10% up to 60%) shifts the curves up and right: faster shortening at every load and a higher load before reaching the isometric point.

(c) Maximum velocity V₀ rises linearly with phosphorylation. Stress rises steeply to about 90% by 20% phosphorylation, then plateaus. More phosphorylated myosin, more cross-bridges. (M4 slide 17; Assignment 4 Q3a)

Lower MLCP (for example via rho kinase): the orange curve, shifted toward the sensitization side. The same Ca²⁺ now gives much more myosin phosphorylation, so contraction rises. Calcium sensitization.

Nitric oxide: cGMP raises MLCP, moving to the purple curve on the desensitization side. The same Ca²⁺ gives far less phosphorylation, so the muscle relaxes. Calcium desensitization.

Ca²⁺ itself does not change in either case; only the phosphatase does. (M4 slide 22; Assignment 4 Q3d)

Rest about −90 mV, peak about +20 mV, total about 200 ms.

0 Na⁺ in through voltage-gated Na⁺ channels. 1 brief K⁺ out. 2 plateau, K⁺ out balanced by Ca²⁺ in through voltage-gated Ca²⁺ channels. 3 Ca²⁺ channels close, K⁺ out continues. 4 rest, only the Na⁺-K⁺ pump.

Phase 2 is flat because positive charge leaves (K⁺) at about the same rate it enters (Ca²⁺). That Ca²⁺ triggers CICR and contraction. (M4 slide 32)

(a) Stretched muscle produces more force at the same Ca²⁺ and its curve sits left of control; short muscle sits right and lower. Stretch raises Ca²⁺ sensitivity, the proposed Frank-Starling mechanism.

(b) At a given velocity the stretched muscle exerts greater tension. At a given load it shortens faster.

(c) Short length reaches zero velocity near 5 g, long length near 10 g. Zero velocity is an isometric contraction: the load equals the maximum force. (M4 slide 37)

Skeletal about 0.3 s on this plot, the lecture’s 10–100 ms range: fast enough for reflexes. Cardiac about 1 s here, about 400 ms at rest in lecture: long enough to eject blood, short enough to relax and refill. Smooth about 5 s: slow and sustained, suited to holding tone in organ walls. (M4 slide 45)

Blocked channels: no extracellular Ca²⁺ influx → nothing to bind and open the RyR, so no CICR → intracellular Ca²⁺ stays low → little Ca²⁺-calmodulin → MLCK not activated → myosin stays dephosphorylated → little force. (slide 12)

Gq ligand: yes. It uses the second route: GPCR → phospholipase C → IP₃ → IP₃ receptor on the SR → stored Ca²⁺ released. That route needs no voltage-gated channel.

Contraction: ↑ free Ca²⁺ → ↑ Ca²⁺-calmodulin → MLCK activated → MLCK phosphorylates the myosin light chain → activated myosin binds actin → cross-bridges and power stroke. (slides 13–14)

Relaxation: SERCA, NCX and PMCA lower free Ca²⁺ → Ca²⁺ leaves calmodulin → MLCK deactivated → MLCP works unopposed → myosin dephosphorylated, inactive → no cross-bridges. (slides 15–16)

Location: smooth muscle regulates on the thick filament, at the myosin head. Skeletal muscle regulates on the thin filament, through troponin and tropomyosin.

Most vessels: NE → alpha-1 → Gq → ↑ IP₃ → ↑ Ca²⁺ release → ↑ MLCK, more gas → contraction. Gq also boosts rho kinase, which inhibits MLCP, less brake.

Skeletal muscle vessels: NE → beta-2 → Gs → ↑ cyclic AMP → cAMP inhibits MLCK, coming off the gas → less force, vessel relaxes. (slides 20–21)

NO is hydrophobic, diffuses into the cell → ↑ cyclic GMP → ↑ MLCP, more brake → more myosin dephosphorylated → relaxation.

Losing NO production in blood vessels is the first sign of the vascular dysfunction that leads to hypertension, coronary artery disease, heart attack, and stroke.

Raising MLCP is calcium desensitization: the calcium-contraction curve shifts right, so more calcium is needed for the same contraction. (slides 21–22)

Smooth muscle: force falls, because cAMP inhibits MLCK. (slide 21)

Cardiac muscle: force rises, because cAMP raises PKA, which phosphorylates the voltage-gated Ca²⁺ channel and RyR, raising calcium influx and release. (slide 40)

The same messenger acts on different machinery: smooth muscle’s force hinges on myosin phosphorylation; cardiac muscle’s hinges on how much Ca²⁺ reaches troponin C.

0 upstroke: Na⁺ in through voltage-gated channels, −90 to about +20 mV. 1 transient repolarization: a little K⁺ out. 2 plateau: K⁺ out balanced by Ca²⁺ in, at least 100 ms. 3 delayed repolarization: Ca²⁺ channels close, K⁺ keeps leaving. 4 rest: Na⁺-K⁺ pump. (slide 32)

The plateau holds because positive charge leaves as K⁺ at the same rate it enters as Ca²⁺. It matters because that entering Ca²⁺ triggers CICR and drives contraction.

Influx normally supplies about 20% of contraction calcium and triggers the other 80% from the SR through CICR. Halving influx means less trigger calcium binding the RyR → less SR release → less Ca²⁺ on troponin C → weaker contraction. The loss is larger than the 10% of total the influx directly supplies. (slide 33)

Removal: SERCA about 70% back into the SR, NCX about 28% out, PMCA about 2% out. A small amount enters the mitochondria. (slide 35)

Resting cell stretch is proportional to active force production. Proposed mechanism: ↑ resting stretch → ↑ filament proximity → ↑ Ca²⁺ sensitivity → ↑ force. (slide 37)

Skeletal muscle’s relationship depends on filament overlap and the number of possible cross-bridges. Cardiac muscle’s appears to depend on filament proximity raising calcium sensitivity. Stretch shifts the calcium-force curve up and left.

NE → beta-1 → ↑ cAMP → ↑ PKA, which phosphorylates:

• Voltage-gated Ca²⁺ channel: more open, more influx → contraction.

• RyR: more open, more release → contraction.

• Phospholamban: switched off, freeing SERCA → faster reuptake → relaxation.

• Troponin I: Ca²⁺ leaves troponin C faster → relaxation.

Parasympathetic: ACh → M₂ → ↓ cAMP → ↓ PKA → less phosphorylation of all four, dampening both contraction and relaxation. By the law of physiological opposites. The effect is weak. (slides 40–41)

Skeletal and smooth can; cardiac cannot. A tetanized heart would not relax for a while, which is a stopped heart. Cardiac and smooth muscle rely almost exclusively on oxidative ATP, making both highly fatigue resistant, and the heart cannot pause to rest. (slide 47)

(a) M₃, Gq, ↑ IP₃ → contraction (airway narrows).

(b) Alpha-1, Gq, ↑ IP₃ → contraction.

(c) Beta-2, Gs, ↑ cAMP → ↓ MLCK → relaxation.

(d) Beta-1, ↑ cAMP → ↑ PKA → stronger contraction and faster relaxation.

(e) M₂, ↓ cAMP → weaker contraction and slower relaxation, a weak effect.

(f) No receptor, ↑ cGMP → ↑ MLCP → relaxation.

Beta-2 → Gs → ↑ cAMP → ↓ MLCK. MLCP keeps working, so phosphorylation falls. The curve drops toward the 10% curve: slower shortening and lower maximal force. Force decreases. (slides 17, 21)

Rho kinase normally inhibits MLCP. Blocking it frees MLCP, so MLCP activity rises, the calcium curve shifts right (desensitization), and force falls. (slides 20, 22)

(a) Phase 0 is Na⁺ influx. Ca²⁺ enters in phase 2.

(b) Phospholamban brakes SERCA. Phosphorylating it releases the brake.

(c) Pacemaker cells start each beat. Autonomic nerves only modulate.

(d) Troponin C binds cardiac Ca²⁺. Calmodulin is smooth muscle.

(a) Phasic, single-unit. (b) Tonic, single-unit. (c) Tonic, single-unit. (d) Multi-unit, for precise control. (slides 4–5)

(1) Stimulus raises free Ca²⁺; (2) Ca²⁺ binds a regulatory protein; (3) more cross-bridging and tension; (4) stimulus ends, Ca²⁺ falls and dissociates; (5) less cross-bridging, relaxation. Skeletal: SR release via DHPR/RyR, troponin C, SERCA. Cardiac: influx plus CICR, troponin C, SERCA/NCX/PMCA. Smooth: influx with CICR or IP₃, calmodulin and MLCK, SERCA/NCX/PMCA and MLCP. (M4 slides 10, 31)

Spindle rather than cylindrical; 5–10 µm thick rather than about 100; 30–200 µm long rather than up to 30 cm; no striations or sarcomeres; dense bodies rather than Z discs; less, scattered SR; no troponin; caveolae rather than T tubules; involuntary rather than voluntary. (M4 slide 2)

Its thin filaments anchor to dense bodies scattered through the cell, with thick filaments between them, rather than to Z discs in repeating sarcomeres. With no repeating bands there is nothing to make stripes. (M4 slide 2)

Phasic: the esophagus, relaxed at baseline and contracting when food is swallowed. Tonic: a sphincter or vascular smooth muscle, contracted at baseline and relaxing when needed. (M4 slide 4)

Single-unit cells are joined by gap junctions. The few stimulated cells depolarize, positive ions flow through the gap junctions into neighbors, and the whole sheet depolarizes and contracts as one unit. (M4 slides 5, 7)

Multi-unit cells are not electrically coupled, so each needs its own neural input. In return the nervous system can choose exactly how many cells contract, giving fine, graded control, as in the eye. (M4 slide 5)

Sympathetic: most vascular contracts (vessels in exercising muscle relax); ocular, some contract and some relax to dilate the pupil; respiratory relaxes; GI and urinary relax. Parasympathetic: some vascular relaxes; ocular acts to constrict the pupil; respiratory contracts; GI and urinary contract. (M4 slide 6)

The circular layer contracts and narrows the tube; the longitudinal layer contracts and shortens it. Alternating between them pushes contents along the digestive tract. (M4 slide 7)

Ca²⁺ is positive like Na⁺, and its inward electrochemical gradient is very strong. Opening voltage-gated Ca²⁺ channels brings positive charge in fast, which depolarizes the membrane just as Na⁺ would. (M4 slide 11)

Slow waves that spike at threshold (force follows the spikes); pacemaker potentials, automaticity (regular rhythmic force); summed action potentials (summed force); subthreshold shifts (force rises as V_m becomes less negative, falls as it becomes more negative). Force can also change with no voltage change, from ligands alone. (M4 slide 11)

Electrical: depolarization → voltage-gated Ca²⁺ channels in caveolae → Ca²⁺ in → Ca²⁺ binds RyR → SR release (CICR). Ligand: agonist → GPCR (Gq) → phospholipase C → DAG + IP₃ → IP₃ receptor on SR → Ca²⁺ release. (M4 slide 12)

Extracellular Ca²⁺ entering the cell binds the ryanodine receptor and opens it, releasing stored Ca²⁺ from the SR. The ligand is Ca²⁺ itself; the channel is the RyR, acting as a ligand-gated channel. (M4 slides 12, 33)

Ca²⁺ binds calmodulin → Ca²⁺-calmodulin activates myosin light-chain kinase → MLCK phosphorylates the myosin light chain on the head → activated myosin binds actin → cross-bridge cycling and power stroke. (M4 slides 13–14)

SERCA (into the SR) does most; the Na⁺-Ca²⁺ exchanger (out of the cell) is second; the plasma membrane Ca²⁺ ATPase is small. (M4 slide 15)

MLCP works all the time. When Ca²⁺ falls, calmodulin releases it and MLCK shuts off, so the phosphatase works unopposed and myosin becomes dephosphorylated. Removing the gas is enough to stop the car. (M4 slide 16)

More force: raise IP₃ (Gq: ACh on M₃, NE on alpha-1); lower cAMP (Gi: NE on alpha-2); inhibit MLCP through rho kinase. Less force: raise cAMP (Gs: NE on beta-2), which inhibits MLCK; raise cGMP (nitric oxide), which raises MLCP. (M4 slides 20–21)

Nitric oxide is a powerful smooth muscle relaxant vital to vascular health. Losing its production in blood vessels is the first sign of vascular dysfunction that leads to hypertension, coronary artery disease, heart attack, and stroke. (M4 slide 21)

Sensitization: less Ca²⁺ gives the same contraction, the curve shifts left (low MLCP). Desensitization: more Ca²⁺ is needed, the curve shifts right (high MLCP). (M4 slide 22)

Outside in: pericardium about 1 mm, myocardium up to 9 mm, endocardium about 0.5 µm. (M4 slide 25)

Shared with skeletal: troponin, T tubules, sarcomeres. Shared with smooth: automaticity, autonomic innervation, gap junctions, long twitch duration. (M4 slides 27–28)

The heart must beat continuously with no neural command, so pacemaker cells must start every beat; without automaticity there is no heartbeat. Smooth muscle can be driven by nerves, hormones, stretch, or local chemicals, so pacemaker cells are needed only in some places, such as the intestines. (M4 slide 28)

0 upstroke: Na⁺ in. 1 transient repolarization: a little K⁺ out. 2 plateau: K⁺ out balanced by Ca²⁺ in. 3 delayed repolarization: Ca²⁺ channels close, K⁺ out continues. 4 rest: Na⁺-K⁺ pump. (M4 slide 32)

Positive charge leaves as K⁺ at about the rate it enters as Ca²⁺, so V_m holds still for 100 ms or more. The Ca²⁺ entering during the plateau triggers CICR and drives contraction. (M4 slide 32)

About 20% enters from the extracellular fluid through voltage-gated Ca²⁺ channels during phase 2. That Ca²⁺ binds the RyR and triggers release of the other 80% from the SR: calcium-induced calcium release. (M4 slide 33)

Resting cell stretch is proportional to active force. Proposed mechanism: stretch → filaments closer together → greater Ca²⁺ sensitivity → more force. Skeletal length-tension depends on filament overlap; cardiac appears to depend on filament proximity. (M4 slide 37)

Voltage-gated Ca²⁺ channel (more influx) and RyR (more release) raise contraction. Phospholamban (switched off, freeing SERCA) and troponin I (Ca²⁺ leaves troponin C faster) speed relaxation. (M4 slide 40)

Phospholamban brakes SERCA. Phosphorylation turns phospholamban off, so the brake comes off and SERCA pumps Ca²⁺ back into the SR faster and more completely. Inhibiting an inhibitor speeds the process. (M4 slide 40)

ACh on M₂ lowers cAMP and PKA, the reverse of sympathetic. Less phosphorylation of the Ca²⁺ channel and RyR gives weaker contraction; less phosphorylation of phospholamban and troponin I gives slower relaxation. The effects are weak. (M4 slide 41)

Skeletal 10–100 ms: fast reflexes and movement. Cardiac about 400 ms: long enough to eject blood, short enough to relax and refill. Smooth about 5 s: holds organ walls contracted for long periods. (M4 slide 45)

A tetanized heart would not relax, and a heart that cannot relax cannot refill: it has stopped. Cardiac muscle relies almost entirely on oxidative ATP, making it highly fatigue resistant, which it must be because it can never rest. (M4 slide 47)