synaptotagmin

Synaptotagmins are a family of integral membrane proteins located on secretory vesicles in neurons and neuroendocrine cells. They function as calcium sensors that trigger neurotransmitter or hormone release. The cytoplasmic region contains two C2 domains, C2A and C2B, following a single transmembrane segment.

In vertebrates, many isoforms exist (Syt1–Syt17). The best studied in the brain are synaptotagmin-1 (Syt1) and synaptotagmin-2 (Syt2), which support fast, synchronous release, and synaptotagmin-7 (Syt7), which contributes to slower, asynchronous release and vesicle replenishment. Other family members show diverse calcium sensitivities and localizations.

Mechanistically, Ca2+ binding to the C2 domains promotes lipid binding and facilitates SNARE complex–driven vesicle fusion. Synaptotagmins interact with SNARE proteins such as syntaxin-1, SNAP-25, and VAMP, positioning them to accelerate fusion in response to Ca2+ influx.

Physiologically, Syt1 predominates at CNS presynaptic terminals mediating fast transmission; Syt2 can partially substitute in some circuits. Syt7 is associated with higher Ca2+ affinity and asynchronous release, as well as roles in vesicle replenishment. Some isoforms also function in dense-core vesicles in neuroendocrine cells. Genetic disruption of Syt1 impairs fast release; loss of Syt7 reduces asynchronous release and high-frequency transmission, illustrating specialized yet overlapping roles.

Clinical and research interest centers on synaptotagmin function in synaptic transmission and plasticity. While specific disease associations vary, alterations in Syt gene expression or function have been investigated in neurological disorders, reflecting their central role in Ca2+-triggered exocytosis.