Journal
SCIENCE
Volume 327, Issue 5973, Pages 1614-1618Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1183765
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Funding
- EU [019055, F2-2009-241498]
- U.K. Medical Research Council
- European Molecular Biology Organization
- Neuro-Bsik Mouse Phenomics Consortium [BSIK03053]
- Medical Research Council [MC_U105178795] Funding Source: researchfish
- MRC [MC_U105178795] Funding Source: UKRI
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Synaptic vesicle fusion in brain synapses occurs in phases that are either tightly coupled to action potentials ( synchronous), immediately following action potentials (asynchronous), or as stochastic events in the absence of action potentials (spontaneous). Synaptotagmin-1, -2, and -9 are vesicle-associated Ca2+ sensors for synchronous release. Here we found that double C2 domain (Doc2) proteins act as Ca2+ sensors to trigger spontaneous release. Although Doc2 proteins are cytosolic, they function analogously to synaptotagmin-1 but with a higher Ca2+ sensitivity. Doc2 proteins bound to N-ethylmaleimide-sensitive factor attachment receptor (SNARE) complexes in competition with synaptotagmin-1. Thus, different classes of multiple C2 domain-containing molecules trigger synchronous versus spontaneous fusion, which suggests a general mechanism for synaptic vesicle fusion triggered by the combined actions of SNAREs and multiple C2 domain-containing proteins.
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