Synaptotagmins

Synaptotagmins are a family of calcium-binding proteins associated with secretory vesicles in neurons and other secretory cells. They function as calcium sensors that couple calcium entry to regulated exocytosis, translating intracellular Ca2+ signals into membrane fusion events that trigger neurotransmitter or hormone release.

Most synaptotagmins share a common topology: a single N-terminal transmembrane domain that anchors the protein to vesicle membranes, with cytosolic C2A and C2B domains that bind calcium and phospholipids. The C2 domains cooperate to promote membrane interactions and regulate SNARE-mediated fusion.

In the nervous system, isoforms specialize in different modes of release. Syt1 (and in some circuits Syt2) mediates fast synchronous release. Syt7 contributes to asynchronous release and sustained release during high-frequency activity. Other isoforms influence vesicle docking, priming, endocytosis, or spontaneous release, illustrating substantial functional diversity within the family.

Mechanistically, synaptotagmins bind calcium through their C2 domains and interact with SNARE proteins, and in some cases with complexins, to regulate fusion pore formation. Calcium-bound synaptotagmins promote vesicle-plasma membrane apposition and lower the energy barrier to fusion.

The synaptotagmin gene family is conserved across animals, with multiple vertebrate genes. Genetic and physiological studies in model organisms show that disruption of specific isoforms produces deficits in evoked release and synaptic plasticity, highlighting their essential role in precise neurotransmission.