Synaptotagmins (SYTs) constitute a family of membrane-trafficking proteins that are characterized by an N-terminal transmembrane region (TMR), a variable linker, and two C-terminal C2 domains - C2A and C2B.

These discrepancies illustrate important distinctions between synaptotagmin isoforms and how they underlie the kinetics of neurotransmission and long-term potentiation.

Subsequent atomic structure analysis of synaptotagmin-1 at 1.9 Å resolution indicated that its C2 domains are composed of a stable eight-stranded β-sandwich with flexible loops emerging from the top and bottom.

In fact, based on sequence similarities and subsequent confirmation by biochemical analyses, only eight synaptotagmins bind to calcium, namely, synaptotagmin-1, -2, -3, -5, -6, -7, -9 and -10.

[13][14] Consistent with this, the kinetics of Ca2+-dependent phospholipid binding activity of the C2A domain in vitro are compatible with the very fast nature of neurotransmitter release (within 200 μs).

The C2B domain binds to phosphatidyl-inositol-3,4,5-triphosphate (PIP3) in the absence of calcium ions, and to phosphatidylinositol bisphosphate (PIP2) in their presence,[16] suggesting that a lipid-interaction switch occurs during depolarization.

Synaptotagmin variants have been implicated in the enhancement of neural connections, leading to long-term potentiation (LTP) in synapses.

Apart from the molecular events mediated by synaptotagmins, these proteins have also been identified to play a large role in the cognitive realm.

Knockout of synaptotagmin proteins in animal models elicited both manic and depressive-like symptoms, characteristic of BD.