NMJ: Ca release mechanism

The neuromuscular junction is composed of the axon terminal of a motor neuron and the motor end-plate of the receiving muscle cell membrane, separated by the synaptic cleft. The collection of muscle fibers innervated by a specific nerve axon is termed a motor unit and it is innervated by a collection of branching, unmyelinated processes from the axon terminal.

The overall process begins when synthesized neurotransmitters are sequestered into vesicles in the axon terminal of a nerve using energy generated from a proton gradient. As the action potential (depolarization via voltage-gated Na⁺ and K⁺ channels) reaches the nerve terminal, voltage-gated calcium channels are activated. This activation increases the influx of Ca²⁺ into the nerve terminal. The rise in intracellular calcium then reacts with the awaiting neurotransmitter vesicles to fuse with the membrane of the nerve membrane. Once fused, the neurotransmitters are released into the synaptic cleft, where they can then diffuse across the cleft to the receptors on the corresponding muscle membrane and exert their effect.

More specifically, neurotransmitter vesicles contain two important proteins, synaptotagmin and synaptobrevin, allowing their docking, fusion, and subsequent release of neurotransmitter from within the axon terminal to the synaptic cleft. As the vesicle migrates closer to the nerve terminal membrane, synaptobrevin binds to a complex of syntaxin and SNAP-25 proteins in the membrane, docking the vesicle. This protein complex subsequently tightens, decreasing the distance between the vesicle and the nerve terminal membrane. Nearby voltage-gated Ca²⁺ channels are triggered by the depolarization of the action potential, causing an increase in Ca²⁺ entry into the nerve terminal, which increases Ca²⁺ concentration surrounding the vesicle. This increased Ca²⁺ concentration then leads to increased Ca²⁺ binding to the vesicle membrane protein synaptotagmin, which triggers fusion of the vesicle with the nerve membrane. After fusion and release of the packaged neurotransmitter across the synaptic cleft, the docking proteins in the nerve membrane use ATP to dissociate from the vesicle, allowing the membrane to be available for binding with a new vesicle.