title: A complexin/synaptotagmin 1 switch controls fast synaptic vesicle exocytosis.
abstract: Ca(2+) binding to synaptotagmin 1 triggers fast exocytosis of synaptic vesicles that have been primed for release by SNARE-complex assembly. Besides synaptotagmin 1, fast Ca(2+)-triggered exocytosis requires complexins. Synaptotagmin 1 and complexins both bind to assembled SNARE complexes, but it is unclear how their functions are coupled. Here we propose that complexin binding activates SNARE complexes into a metastable state and that Ca(2+) binding to synaptotagmin 1 triggers fast exocytosis by displacing complexin from metastable SNARE complexes. Specifically, we demonstrate that, biochemically, synaptotagmin 1 competes with complexin for SNARE-complex binding, thereby dislodging complexin from SNARE complexes in a Ca(2+)-dependent manner. Physiologically, increasing the local concentration of complexin selectively impairs fast Ca(2+)-triggered exocytosis but retains other forms of SNARE-dependent fusion. The hypothesis that Ca(2+)-induced displacement of complexins from SNARE complexes triggers fast exocytosis accounts for the loss-of-function and gain-of-function phenotypes of complexins and provides a molecular explanation for the high speed and synchronicity of fast Ca(2+)-triggered neurotransmitter release.
authors.affiliation: The Center for Basic Neuroscience, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Jiong
authors.initials: J
authors.lastname: Tang
authors.forename: Anton
authors.initials: A
authors.lastname: Maximov
authors.forename: Ok-Ho
authors.initials: OH
authors.lastname: Shin
authors.forename: Han
authors.initials: H
authors.lastname: Dai
authors.forename: Josep
authors.initials: J
authors.lastname: Rizo
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Südhof
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D001665:Binding Sites / Q000502:physiology; D001667:Binding, Competitive / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D002490:Central Nervous System / Q000378:metabolism; D005089:Exocytosis / Q000502:physiology*; D006801:Humans; D046911:Macromolecular Substances / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D017729:Presynaptic Terminals / Q000378:metabolism*; D051381:Rats; D050600:SNARE Proteins / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology*; D013572:Synaptic Vesicles / Q000378:metabolism*; D050863:Synaptotagmin I / Q000378:metabolism*; D013997:Time Factors
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D046911:Macromolecular Substances; D009419:Nerve Tissue Proteins; D050600:SNARE Proteins; D050863:Synaptotagmin I; C494311:Syt1 protein, mouse; C095992:complexin I; D002118:Calcium