The Synaptic Vesicle Release Machinery

Extensive research has yielded crucial insights into the mechanism of neurotransmitter release, and working models for the functions of key proteins involved in release. The SNAREs Syntaxin-1, Synaptobrevin, and SNAP-25 play a central role in membrane fusion, forming SNARE complexes that bridge the vesicle and plasma membranes and that are disassembled by NSF-SNAPs. Exocytosis likely starts with Syntaxin-1 folded into a self-inhibited closed conformation that binds to Munc18-1. Munc13s open Syntaxin-1, orchestrating SNARE complex assembly in an NSF-SNAP-resistant manner together with Munc18-1. In the resulting primed state, with partially assembled SNARE complexes, fusion is inhibited by Synaptotagmin-1 and Complexins, which also perform active functions in release. Upon influx of Ca2+, Synaptotagmin-1 activates fast release, likely by relieving the inhibition caused by Complexins and cooperating with the SNAREs in bringing the membranes together. Although alternative models exist and fundamental questions remain unanswered, a definitive description of the basic release mechanism may be available soon.