neuromuscular junction

The NMJ consists of a presynaptic motor neuron terminal, synaptic cleft, and postsynaptic motor endplate on the muscle fiber. Action potentials in the motor neuron cause voltage-gated Ca2+ channels to open, triggering ACh release from synaptic vesicles via exocytosis. ACh diffuses across the cleft and binds nicotinic ACh receptors (ligand-gated Na+/K+ channels) on the postsynaptic membrane, causing depolarization (endplate potential) that, if threshold is reached, triggers a muscle action potential via voltage-gated Na+ channels, leading to excitation-contraction coupling. Acetylcholinesterase in the synaptic cleft rapidly degrades ACh, terminating the signal.

Clinical relevance: Myasthenia gravis is an autoimmune disease with antibodies against postsynaptic nicotinic ACh receptors, causing fatigable weakness that improves with rest and worsens with repetitive use (decremental response on repetitive nerve stimulation); treated with acetylcholinesterase inhibitors (e.g., pyridostigmine). Lambert-Eaton myasthenic syndrome involves antibodies against presynaptic voltage-gated Ca2+ channels, reducing ACh release, causing proximal weakness that improves with repeated use (incremental response) and is associated with small cell lung cancer. Botulinum toxin blocks ACh release presynaptically (flaccid paralysis), while tetanus toxin blocks inhibitory neurotransmitter release in the CNS. Organophosphate poisoning inhibits acetylcholinesterase, causing excess ACh accumulation (SLUDGE syndrome, muscle fasciculations then paralysis). Neuromuscular blockers used in anesthesia include depolarizing (succinylcholine) and nondepolarizing (rocuronium, vecuronium) agents acting at nicotinic receptors.