Ca²⁺-Triggered Synaptic Vesicle Fusion Initiated by Release of Inhibition

Recent structural and functional studies of the synaptic vesicle fusion machinery suggest an inhibited tripartite complex consisting of neuronal soluble N-ethylmaleimide sensitive factor attachment protein receptors (SNAREs), synaptotagmin, and complexin prior to Ca²⁺-triggered synaptic vesicle fusion. We speculate that Ca²⁺-triggered fusion commences with the release of inhibition by Ca²⁺ binding to synaptotagmin C2 domains. Subsequently, fusion is assisted by SNARE complex zippering and by active membrane remodeling properties of synaptotagmin. This additional, inhibitory role of synaptotagmin may be a general principle since other recent studies suggest that Ca²⁺ binding to extended synaptotagmin C2 domains enables lipid transport by releasing an inhibited state of the system, and that Munc13 may nominally be in an inhibited state, which is released upon Ca²⁺ binding to one of its C2 domains.