SYT2

Synaptotagmin-2 (Syt2) is a member of the synaptotagmin family of calcium-binding proteins that regulate neurotransmitter release. The human SYT2 gene encodes the synaptotagmin-2 protein, which is anchored to synaptic vesicles by a single transmembrane domain and contains two cytoplasmic C2 domains that bind calcium and phospholipids.

Mechanism and role: In response to calcium influx, the C2 domains of Syt2 interact with SNARE complexes and membrane lipids to accelerate vesicle fusion, supporting fast, synchronous neurotransmitter release at many chemical synapses. Syt2 contributes to release fidelity and exhibits distinct calcium sensitivity and kinetics compared with other family members in certain synapses. In mouse models, loss of Syt2 reduces fast synchronous release at select brainstem and cerebellar synapses, with partial compensation by synaptotagmin-1 in others, indicating overlapping yet specialized functions among synaptotagmins.

Expression and localization: Syt2 is broadly expressed in the central nervous system, with higher levels in brainstem, cerebellum, and spinal cord and comparatively lower levels in cortex. It is present at various peripheral synapses as well, reflecting its role in fast neurotransmission across diverse neural circuits.

Clinical significance: Mutations in SYT2 have been linked to congenital myasthenic syndromes and other neuromuscular transmission disorders, causing impaired evoked transmitter release and fatigable weakness. The gene remains a focus of study for understanding the molecular basis of rapid, reliable synaptic transmission.

Evolution and family: Syt2 is part of the conserved synaptotagmin family, with orthologs in mammals and other vertebrates. Its structure and function reflect shared features of Ca2+-dependent membrane fusion regulators among synaptotagmins.