Skeletal Muscle: NMJ and EC Coupling

Skeletal Muscle: Neuromuscular Junction and Excitation-Contraction Coupling

Neuromuscular Junction

Each skeletal muscle fibre is innervated by a single motor neuron, but each motor neuron may innervate multiple fibres (a motor unit). The neuromuscular junction (NMJ) is a specialised synapse between the axon terminal and the muscle fibre.

Sequence of events at the NMJ:

1. AP arrives at the motor axon terminal.
2. Voltage-gated Ca²⁺ channels open → Ca²⁺ enters the bouton.
3. SNARE-mediated exocytosis releases ACh into the synaptic cleft.
4. ACh diffuses to the junctional folds on the muscle (post-junctional membrane).
5. ACh binds nicotinic ACh receptors (nAChR, ionotropic) → Na⁺ influx → local depolarisation (end-plate potential, EPP).
6. The EPP depolarises adjacent extrajunctional voltage-gated Na⁺ channels → muscle AP propagates in both directions along sarcolemma.
7. AChE in the synaptic cleft rapidly degrades ACh → terminates signal.

Myasthenia gravis: autoimmune antibodies against nAChR (or MuSK) → reduced receptor density → smaller EPPs → progressive muscle weakness and rapid fatigue. Cardinal signs: ptosis (eyelid), diplopia, fatigable proximal limb weakness. Treated with AChE inhibitors (neostigmine, pyridostigmine) and immunosuppression.

Excitation-Contraction (EC) Coupling

The muscle AP propagates along the sarcolemma and into T-tubules (transverse tubules) — deep invaginations at the A-I junction. In the T-tubule membrane, dihydropyridine receptors (DHPR, voltage-sensors / L-type Ca²⁺ channels) are mechanically coupled to ryanodine receptors (RYR1) on the adjacent sarcoplasmic reticulum (SR) terminal cisternae. Depolarisation of DHPR causes conformational change → opens RYR1 → Ca²⁺ floods from SR into cytoplasm (Ca²⁺ spark → global Ca²⁺ transient). Intracellular [Ca²⁺] rises from ~10⁻⁷ M (rest) to ~10⁻⁵ M.

Ca²⁺ binds troponin C → conformational change in troponin-tropomyosin complex → tropomyosin moves off actin's myosin-binding sites → cross-bridge cycle begins. Relaxation occurs when SERCA pumps (SR Ca²⁺-ATPase) actively pump Ca²⁺ back into SR → [Ca²⁺] falls → troponin releases Ca²⁺ → tropomyosin returns to blocking position.

Sarcomere Structure and Contraction

The sarcomere is the functional unit of contraction (Z-line to Z-line). During contraction: I-bands (actin only) shorten, H-zone (myosin only) shortens, Z-lines come closer, but A-band (myosin-containing region) remains constant. The sliding filament theory: actin and myosin filaments do not change length — they slide past each other. Twitch summation: if a second stimulus arrives before the muscle fully relaxes, the twitches summate (mechanical summation). Tetanus: rapid stimulation → sustained contraction (unfused tetanus → fused tetanus).