As it enters the muscle and approaches its target fibers, each α–motor neuron axon divides into branches that innervate many individual muscle fibers. Each branch loses its myelin sheath and further subdivides into many presynaptic boutons, which contain ACh-loaded synaptic vesicles and face the surface of the muscle fiber at the NMJ. The synaptic bouton and the muscle surface are separated by the synaptic cleft, which contains AChE and proteins and proteoglycans involved in stabilizing the NMJ structure. The NMJ postsynaptic membrane has characteristic deep folds, and the AChR is densely packed at the fold top. When the nerve action potential reaches the synaptic bouton, ACh is released into the synaptic cleft, where it diffuses to reach and bind the AChR. ACh binding triggers the AChR ion channel opening, permitting influx of Na⁺ into the muscle fiber. The resulting EPP activates voltage-gated Na⁺ channels at the bottom of the folds, leading to further Na⁺ influx and spreading of the action potential along the muscle fiber. Other proteins, including Rapsyn, MuSK, and agrin, which are involved in AChR clustering, are also present on the muscle membrane in close proximity to the AChR. MASC, myotube-associated specificity component; RATL, rapsyn-associated transmembrane linker. Figure modified with permission from Lippincott Williams and Wilkins (126).