Neuromuscular Junction Organization
Skeletal muscle fibers receive nerve supply through large, myelinated nerve fibers originating in the ventral horn of the spinal cord. Each nerve fiber enters the muscle belly where the nerve then supplies branches to activate anywhere from three to hundreds of targeted myofibers. The point at which the branched nerve axon connects with the skeletal muscle is called the neuromuscular junction. As the action potential fires across the neuromuscular junction and into the skeletal muscle fiber, the muscle fiber relays the excitatory stimulus bidirectionally toward both muscle fiber endings. This nerve-muscle organization is universal, with a single neuromuscular junction per myofiber, aside from 2% of muscle fibers which receive input from more than one neuromuscular junction.
The neuromuscular junction, also called motor end plate, is a specialized chemical synapse that releases acetylcholine from the axon ending to bind a postsynaptic muscle receptor. These junctions demonstrate very unique architecture. Axons terminate in a knob-like invagination of the muscle fiber without penetration of the muscle fiber membrane. The myelin sheath terminates near the neuromuscular junction; at this point, three to five Schwann cells seamlessly continue wrapping the terminal nerve axon while extending into the knob-like space between the nerve and myofiber membrane.1 Schwann cells function to store the neurotransmitter acetylcholine, clear cell debris, decode competing synaptic stimuli, and promote muscle fiber survival.2
The invaginated muscle membrane has several names, including synaptic trough and synaptic gutter. The junction between the presynaptic nerve axon terminal and postsynaptic muscle membrane is referred to as the synaptic space or synaptic cleft. This space is 20 to 30 nm wide and performs all chemical communication between nerve and muscle.3 At the base of the gutter are smaller folds in the muscle membrane called subneural clefts. These folds markedly increase the total surface area able to respond to acetylcholine.3
Acetylcholine is an excitatory neurotransmitter of the muscle fiber membrane. The lifecycle of neurosynaptic acetylcholine is complex and will be explored in depth in the next section, but it is essentially stored in presynaptic axon vesicles and released into the synapse when stimulated by an action potential. The synaptic cleft has a reserve of acetylcholinesterase enzymes which degrade the large quantities of synaptic acetylcholine only milliseconds after being released effectively terminating the excitatory signal.
Nerve impulses, called action potentials, fire down the axon until arriving at the presynaptic motor plate. The presynaptic membrane architecture is highly organized and specific to its function. Active zones, visualized as dense localized multimolecular complexes on electron microscopy, bind large amounts of vesicles (i.e., quanta) to be released into the synaptic space.4 To each side of the active zones are transmembrane protein channels called voltage-gated calcium channels. When sodium moves into the axon, depolarizing the motor endplate, these voltage-gated calcium ...