Nerve-Muscle Physiology — 15-Mark Answer

1. Resting Membrane Potential (RMP)

a) Na⁺-K⁺ ATPase Pump (Electrogenic)

• Pumps 3 Na⁺ out and 2 K⁺ in per cycle → net positive charge loss → inside becomes negative
• Creates concentration gradients:
  • Na⁺: 142 mEq/L (outside) vs. 14 mEq/L (inside)
  • K⁺: 4 mEq/L (outside) vs. 140 mEq/L (inside)

b) K⁺ Leak Channels

• Resting membrane is 50–100× more permeable to K⁺ than Na⁺ via K⁺ leak channels
• K⁺ diffuses outward down its concentration gradient → interior becomes negative

c) Impermeant Anions

• Large negatively charged proteins, phosphates, and sulfates trapped inside the cell contribute to the net negative intracellular charge

2. Action Potential (AP)

Stages:

Ionic Mechanisms:

• Voltage-gated Na⁺ channels: Activation gate opens rapidly at threshold → Na⁺ conductance increases 5000-fold → explosive depolarization. Inactivation gate closes within < 1 ms.
• Voltage-gated K⁺ channels: Open slowly after Na⁺ channels activate → K⁺ efflux restores negative potential (repolarization)
• At peak AP: Na⁺/K⁺ conductance ratio > 1000:1 (favoring Na⁺ influx)
• During repolarization: ratio reverses → high K⁺ conductance

3. Threshold and Excitability

• A stimulus must depolarize the membrane to the threshold (~ −55 mV) to trigger an AP
• Subthreshold stimuli produce local potentials that fade without propagation
• All-or-none law: Once threshold is reached, a full AP is generated regardless of stimulus strength

Refractory Periods:

• Absolute Refractory Period: Immediately after an AP — Na⁺ channels are inactivated; no new AP can be elicited regardless of stimulus strength
• Relative Refractory Period: Follows the absolute refractory period — K⁺ channels still open; a stronger-than-normal stimulus can elicit an AP; membrane is hyperpolarized

4. Propagation of Action Potential

• Unmyelinated fibers: AP spreads by local current flow along the entire membrane (slow conduction)
• Myelinated fibers: Myelin acts as insulator; current jumps between Nodes of Ranvier → saltatory conduction → much faster propagation (up to ~70 m/sec in large myelinated fibers vs. 3–5 m/sec in skeletal muscle)

5. Neuromuscular Junction (NMJ)

Structure:

• Motor end plate: Branching axon terminals invaginate into the muscle fiber surface
• Synaptic cleft: 20–30 nm wide; contains acetylcholinesterase
• Subneural clefts: Folds in muscle membrane increase surface area for ACh action
• Synaptic vesicles: ~300,000 per terminal; each contains acetylcholine (ACh)

Transmission (Steps):

1. Nerve impulse arrives → depolarizes axon terminal
2. Voltage-gated Ca²⁺ channels open → Ca²⁺ influx into terminal
3. Ca²⁺ activates calmodulin-dependent kinase → phosphorylates synapsin proteins → ~125 ACh vesicles released by exocytosis
4. ACh binds nicotinic receptors (pentameric: 2α, β, δ, γ subunits) on postsynaptic membrane
5. Receptor channels open → large Na⁺ influx (and smaller K⁺ efflux) → End Plate Potential (EPP) of 50–75 mV
6. EPP triggers voltage-gated Na⁺ channels → muscle action potential
7. Acetylcholinesterase in synaptic cleft rapidly destroys ACh → termination of signal (within milliseconds)

End Plate Potential (EPP):

• A local depolarization of 50–75 mV at the motor end plate
• Normally suprathreshold → always initiates a muscle AP (unlike CNS synapses)
• If EPP is too weak (e.g., Myasthenia Gravis), no AP is generated

6. Muscle Action Potential & Excitation-Contraction Coupling

Muscle AP characteristics:

• Duration: 1–5 ms (5× longer than nerve AP)
• Velocity: 3–5 m/sec
• RMP: −80 to −90 mV

Excitation-Contraction Coupling:

1. Muscle AP spreads along sarcolemma and into T-tubules (transverse tubules — extensions of cell membrane)
2. T-tubule depolarization activates dihydropyridine receptors (DHPR/voltage sensors) in T-tubule membrane
3. DHPR mechanically activates ryanodine receptors (RyR) on terminal cisternae of sarcoplasmic reticulum (SR)
4. SR releases Ca²⁺ into sarcoplasm → Ca²⁺ binds troponin C on thin filaments
5. Conformational change in troponin-tropomyosin complex → exposes actin active sites
6. Myosin heads (energized by ATP) bind actin → cross-bridge cycling → muscle contraction (sliding filament mechanism)
7. When AP ends: SR Ca²⁺-ATPase (SERCA pump) re-sequesters Ca²⁺ → relaxation

Summary Diagram (Key Values)

Clinical Correlate — Myasthenia Gravis

• Autoimmune destruction of nicotinic ACh receptors at NMJ
• EPPs too weak to trigger muscle AP → progressive muscle weakness
• Treatment: Neostigmine (anticholinesterase) → ACh accumulates → partially restores EPP
• Death may result from respiratory muscle failure