Structure of the neuromuscular junction: function and cooperative mechanisms in the synapse

As an overview of the structure of the neuromuscular junction, three items are described focusing on cooperative mechanisms involving the synapse and leading to muscle contraction: (1) presynaptic acetylcholine release regulated by vesicle cycling (exocytosis and endocytosis); the fast-mode of endocytosis requires a large influx of external Ca2+ and is promoted by the activation of G protein-coupled receptors and receptor tyrosine kinases; (2) postsynaptic acetylcholine receptor clustering mediated by the muscle-specific, Dok7-stimulated tyrosine kinase (MuSK) through two signaling mechanisms: one via agrin-Lrp4-MuSK (Ig1/2 domains) and the second via Wnt-MuSK (Frizzled-like cysteine-rich domain)-adaptor Dishevelled; Wnts/MuSK and Lrp4 direct a retrograde signal to presynaptic differentiation; (3) muscle contractile machinery regulated by Ca2+-release and Ca2+-influx channels, including the depolarization-activated ryanodine receptor-1 and the receptor-and/or store-operated transient receptor potential canonical. The first mechanism is dysfunctional in Lambert-Eaton myasthenic syndrome, the second in anti-acetylcholine receptor-negative myasthenia gravis (MG), and the third in thymoma-associated MG.