The Synaptic Vesicle Release Machinery

• Published in: Annual review of biophysics Vol. 44; no. 1; pp. 339 - 367
• Main Authors: Rizo, Josep, Xu, Junjie
• Format: Journal Article
• Language: English
• Published: United States Annual Reviews 22.06.2015
• Subjects: Animals; Cell Membrane - metabolism; Complexin; Membrane Fusion; Munc13; Munc18; Nerve Tissue Proteins - metabolism; Protein Binding; SNARE Proteins - metabolism; SNAREs; Synaptic Transmission; Synaptic Vesicles - chemistry; Synaptic Vesicles - metabolism; Synaptotagmin; Synaptotagmins - metabolism; Synaptotagmin; Munc18; Complexin; Munc13; SNAREs; membrane fusion
• ISSN: 1936-122X; 1936-1238
• DOI: 10.1146/annurev-biophys-060414-034057

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 Ca 2+ , 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.