Ca²⁺ sensors: Synaptotagmins

Synaptotagmin is a synaptic vesicle membrane protein that is postulated to function as a calcium (Ca²⁺) sensor for neurotransmitter release. This protein contains two Ca²⁺-binding domains (C2A, C2B) in its cytoplasmic region. Genetic studies provide strong evidence supporting the idea that synaptotagmin is the Ca²⁺ sensor for the fast synchronous component of evoked transmitter release. In addition, synaptotagmin appears to be involved in docking and priming (by clamping spontaneous fusion) of synaptic vesicles and regulating fusion pores as well as vesicle endocytosis. In vitro studies demonstrate that synaptotagmin binds to phospholipid membranes in the presence and absence of Ca²⁺. Furthermore, in response to Ca²⁺, the tips of synaptotagmin C2 domains penetrate lipid bilayers, altering the membrane curvature. Synaptotagmin also binds to the soluble Nethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex that is believed to be the core fusion machinery, although the findings on the Ca²⁺ dependency of binding of synaptotagmin to SNARE have been inconsistent and controversial. Taken together, synaptotagmin appears to trigger a fast synchronous component of transmitter release by binding to Ca²⁺, probably through the interactions with both membranes and SNAREs.