Synaptotagmin-1 functions as a Ca2+ sensor for spontaneous release

Nat Neurosci. 2009 Jun;12(6):759-66. doi: 10.1038/nn.2320.


Spontaneous 'mini' release occurs at all synapses, but its nature remains enigmatic. We found that >95% of spontaneous release in murine cortical neurons was induced by Ca2+-binding to synaptotagmin-1 (Syt1), the Ca2+ sensor for fast synchronous neurotransmitter release. Thus, spontaneous and evoked release used the same Ca2+-dependent release mechanism. As a consequence, Syt1 mutations that altered its Ca2+ affinity altered spontaneous and evoked release correspondingly. Paradoxically, Syt1 deletions (as opposed to point mutations) massively increased spontaneous release. This increased spontaneous release remained Ca2+ dependent but was activated at lower Ca2+ concentrations and with a lower Ca2+ cooperativity than synaptotagmin-driven spontaneous release. Thus, in addition to serving as a Ca2+ sensor for spontaneous and evoked release, Syt1 clamped a second, more sensitive Ca2+ sensor for spontaneous release that resembles the Ca2+ sensor for evoked asynchronous release. These data suggest that Syt1 controls both evoked and spontaneous release at a synapse as a simultaneous Ca2+-dependent activator and clamp of exocytosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism*
  • Calcium / pharmacology
  • Calcium Signaling / genetics*
  • Cerebral Cortex / metabolism*
  • Cerebral Cortex / ultrastructure
  • Dose-Response Relationship, Drug
  • Exocytosis / genetics
  • Membrane Fusion / drug effects
  • Membrane Fusion / physiology
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Mice
  • Neurotransmitter Agents / metabolism
  • Presynaptic Terminals / metabolism*
  • Presynaptic Terminals / ultrastructure
  • Synaptic Membranes / genetics
  • Synaptic Membranes / metabolism
  • Synaptic Transmission / genetics*
  • Synaptotagmin I / genetics
  • Synaptotagmin I / metabolism*


  • Neurotransmitter Agents
  • Synaptotagmin I
  • Syt1 protein, mouse
  • Calcium