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Acetylcholine release: Physiology

Acetylcholine is synthesized from choline and acetyl coenzyme A, catalyzed by the enzyme O-acetyl transferase. Once synthesized, the acetylcholine molecules are stored in synaptic vesicles in high concentration near the motor endplate. SNAREs (soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptors) are a multigene family of neuron-specific phosphoproteins and are the most abundant proteins on synaptic vesicles. SNARE proteins are able to interact in vitro with lipid and protein components of synaptic vesicles and with various cytoskeletal proteins, including actin.Synapsin I is a phosphorylated protein found in nerve terminals. Its role is to attach the synaptic vesicles to elements of the cytoskeleton. Synapsin I has a binding site for a calcium/calmodulin-dependent protein kinase II. Phosphorylation of synapsinI decreases its binding affinity for synapsin I to the synaptic vesicle and facilitates the release of acetylcholine.Synaptotagmin, synaptophysins, and synaptobrevin are other integral vesicular membrane proteins involved in the docking of the vesicles at the release sites and the formation of the fusion pore.

The anatomy of the neuromuscular junction (NMJ) consists of a prejunctional motor nerve ending separated from the highly folded post-junctional membrane of the skeletal muscle by a synaptic cleft. In the NMJ, nicotinic acetylcholine receptors are located both at the pre (neural) and post-junctional (muscle) sites. In order for neuromuscular transmission to occur, an action potential needs to be generated by the motor nerve terminal. Influx of calcium ions leads to a cascade of events that ultimately leads to release of acetylcholine by the nerve by mechanism described above. Once the action potential is generated and acetylcholine is released, the molecules travel across the synaptic cleft, binding to receptors on the post-junctional membrane on the motor endplate. In the case of nicotinic receptors, both alpha subunits must be bound. Binding allows for a conformational change in the structure of the receptor. This structural change results in a change in membrane permeability to K+ and Na+ ions. The transmembrane potential in the post-junctional membrane changes from -90mV to -45mV, at which point the action potential propagates across the muscle fiber leading to contraction.


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