Position of UNC-13 in the active zone regulates synaptic vesicle release probability and release kinetics

The presynaptic active zone proteins UNC-13/Munc13s are essential for synaptic vesicle (SV) exocytosis by directly interacting with SV fusion apparatus. An open question is how their association with active zones, hence their position to Ca(2+) entry sites, regulates SV release. The N-termini of major UNC-13/Munc13 isoforms contain a non-calcium binding C(2)A domain that mediates protein homo- or hetero-meric interactions. Here, we show that the C(2)A domain of Caenorhabditis elegans UNC-13 regulates release probability of evoked release and its precise active zone localization. Kinetics analysis of SV release supports that the proximity of UNC-13 to Ca(2+) entry sites, mediated by the C(2)A-domain containing N-terminus, is critical for accelerating neurotransmitter release. Additionally, the C(2)A domain is specifically required for spontaneous release. These data reveal multiple roles of UNC-13 C(2)A domain, and suggest that spontaneous release and the fast phase of evoked release may involve a common pool of SVs at the active zone. DOI: http://dx.doi.org/10.7554/eLife.01180.001