Synaptotagmin arrests the SNARE complex before triggering fast, efficient membrane fusion in response to Ca2+

Nat Struct Mol Biol. 2008 Aug;15(8):827-35. doi: 10.1038/nsmb.1463. Epub 2008 Jul 11.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism*
  • Catalysis
  • Cell Membrane / metabolism
  • Electrophysiology
  • Exocytosis
  • Hippocampus / metabolism
  • Lipids / chemistry
  • Mice
  • Mice, Knockout
  • Models, Biological
  • Plasmids / metabolism
  • Rats
  • SNARE Proteins / metabolism*
  • Synaptotagmins / metabolism
  • Synaptotagmins / physiology*


  • Lipids
  • SNARE Proteins
  • Synaptotagmins
  • Calcium