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 Ca 2+-binding to synaptotagmin-1 (Syt1), the Ca 2 + sensor for fast synchronous neurotransmitter release. Thus, spontaneous and evoked release used the same Ca 2+ -dependent release mechanism. As a consequence, Syt1 mutations that altered its Ca 2+ affinity altered spontaneous and evoked release correspondingly. Paradoxically, Syt1 deletions (as opposed to point mutations) massively increased spontaneous release. This increased spontaneous release remained Ca 2+ dependent but was activated at lower Ca 2+concentrations and with a lower Ca 2 + cooperativity than synaptotagmin-driven spontaneous release. Thus, in addition to serving as a Ca 2+ senso r for spontaneous and evoked release, Syt1 clamped a second, more sensitive Ca 2+ sensor for spontaneous release that resembles the Ca 2+ sensor for evoked asynchronous release. These data suggest that Syt1 controls both evoked and spontaneous release at a synapse as a simultaneous Ca 2+ -dependent activator and clamp of exocytosis.
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