title: The Synaptic Vesicle Release Machinery.
abstract: 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.
authors.affiliation: Departments of Biophysics, Biochemistry, and Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390; email: jose@arnie.swmed.edu.
authors.forename: Josep
authors.initials: J
authors.lastname: Rizo
authors.forename: Junjie
authors.initials: J
authors.lastname: Xu
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D008561:Membrane Fusion; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011485:Protein Binding; D050600:SNARE Proteins / Q000378:metabolism*; D009435:Synaptic Transmission; D013572:Synaptic Vesicles / Q000737:chemistry / Q000378:metabolism*; D050857:Synaptotagmins / Q000378:metabolism
chemical_list: D009419:Nerve Tissue Proteins; D050600:SNARE Proteins; D050857:Synaptotagmins
keywords: Complexin; Munc13; Munc18; SNAREs; Synaptotagmin; membrane fusion