Synaptotagmin-1 functions as a Ca2+ sensor for  spontaneous release.
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.
Xu
Jun
J
Department of Molecular & Cellular Physiology, Stanford University, Palo Alto, California, USA.
Pang
Zhiping P
ZP
Shin
Ok-Ho
OH
Südhof
Thomas C
TC
D000818:Animals; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology; D020013:Calcium Signaling / Q000235:genetics*; D002540:Cerebral Cortex / Q000378:metabolism* / Q000648:ultrastructure; D004305:Dose-Response Relationship, Drug; D005089:Exocytosis / Q000235:genetics; D008561:Membrane Fusion / Q000187:drug effects / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018377:Neurotransmitter Agents / Q000378:metabolism; D017729:Presynaptic Terminals / Q000378:metabolism* / Q000648:ultrastructure; D013570:Synaptic Membranes / Q000235:genetics / Q000378:metabolism; D009435:Synaptic Transmission / Q000235:genetics*; D050863:Synaptotagmin I / Q000235:genetics / Q000378:metabolism*
D018377:Neurotransmitter Agents; D050863:Synaptotagmin I; C494311:Syt1 protein, mouse; D002118:Calcium