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Regulated exocytosis, which underlies many intercellular signaling events, is a tightly controlled process often triggered by calcium ion(s) (Ca 2+ ). Despite considerable insight into the central components involved, namely, the core fusion machinery [soluble N -ethylmaleimide-sensitive factor attachment protein receptor (SNARE)] and the principal Ca 2+ sensor [C2-domain proteins like synaptotagmin (Syt)], the molecular mechanism of Ca 2+ -dependent release has been unclear. Here, we report that the Ca 2+ -sensitive oligomers of Syt1, a conserved structural feature among several C2-domain proteins, play a critical role in orchestrating Ca 2+ -coupled vesicular release. This follows from pHluorin-based imaging of single-vesicle exocytosis in pheochromocytoma (PC12) cells showing that selective disruption of Syt1 oligomerization using a structure-directed mutation (F349A) dramatically increases the normally low levels of constitutive exocytosis to effectively occlude Ca 2+ -stimulated release. We propose a parsimonious model whereby Ca 2+ -sensitive oligomers of Syt (or a similar C2-domain protein) assembled at the site of docking physically block spontaneous fusion until disrupted by Ca 2+ Our data further suggest Ca 2+ -coupled vesicular release is triggered by removal of the inhibition, rather than by direct activation of the fusion machinery.

Synaptotagmin oligomerization is essential for calcium control of regulated exocytosis