title: Synaptotagmin arrests the SNARE complex before triggering fast, efficient membrane fusion in response to Ca2+.
abstract: Neuronal communication is mediated by Ca(2+)-triggered fusion of transmitter-filled synaptic vesicles with the presynaptic plasma membrane. Synaptotagmin I functions as a Ca(2+) sensor that regulates exocytosis, whereas soluble N-ethylmaleimide-sensitive factor attachment protein (SNAP) receptor (SNARE) proteins in the vesicle and target membrane assemble into complexes that directly catalyze bilayer fusion. Here we report that, before the Ca(2+) trigger, synaptotagmin interacts with SNARE proteins in the target membrane to halt SNARE complex assembly at a step after donor vesicles attach, or dock, to target membranes. This results in fusion complexes that, when subsequently triggered by Ca(2+), drive rapid, highly efficient lipid mixing. Ca(2+)-independent interactions with SNAREs also predispose synaptotagmin to selectively penetrate the target membrane in response to Ca(2+); we demonstrate that Ca(2+)-synaptotagmin must insert into the target membrane to accelerate SNARE-catalyzed fusion. These findings demonstrate that Ca(2+) converts synaptotagmin from a clamp to a trigger for exocytosis.
authors.affiliation: Howard Hughes Medical Institute and Department of Physiology, University of Wisconsin, Madison, 1300 University Avenue, SMI 129, Madison, Wisconsin 53706, USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Chicka
authors.forename: Enfu
authors.initials: E
authors.lastname: Hui
authors.forename: Huisheng
authors.initials: H
authors.lastname: Liu
authors.forename: Edwin R
authors.initials: ER
authors.lastname: Chapman
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002384:Catalysis; D002462:Cell Membrane / Q000378:metabolism; D004594:Electrophysiology; D005089:Exocytosis; D006624:Hippocampus / Q000378:metabolism; D008055:Lipids / Q000737:chemistry; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D010957:Plasmids / Q000378:metabolism; D051381:Rats; D050600:SNARE Proteins / Q000378:metabolism*; D050857:Synaptotagmins / Q000378:metabolism / Q000502:physiology*
chemical_list: D008055:Lipids; D050600:SNARE Proteins; D050857:Synaptotagmins; D002118:Calcium