Synaptotagmin: A Ca2+ sensor that triggers exocytosis?

Neuronal exocytosis is triggered by Ca2+ ions, and members of the synaptotagmin gene family (>13 isoforms) are leading candidates to serve as the Ca2+ sensors that trigger neurotransmitter release. Synaptotagmin I is the best characterized isoform, and is the most abundant Ca2+-binding protein on secretory organelles. Genetic studies indicate that synaptotagmin I functions at several stages in the synaptic-vesicle cycle, including a key function between the docking and fusion of vesicles, which is consistent with its proposed role as a Ca2+ sensor during exocytosis. Synaptotagmin I also has a key role in endocytosis after fusion. The structures of the Ca2+-sensing domains of synaptotagmin — C2A and C2B — and the Ca2+-binding sites of these domains have been determined. Studies are now beginning to uncover how Ca2+ regulates the interaction of synaptotagmin with effectors. Ca2+ triggers the partial penetration of the Ca2+-binding loops of the C2 domains of synaptotagmin into lipid bilayers with very rapid kinetics. Penetration into the plasma membrane might pull bilayers together to facilitate fusion. The C2 domains of synaptotagmin also interact directly with components of the SNARE complex, which is thought to form the core of a conserved membrane fusion machine. These interactions might facilitate the assembly of SNARE complexes to accelerate fusion. Efforts at present are directed towards the reconstitution of Ca2+-triggered membrane fusion. A defined and reduced model system might make it possible to determine whether synaptotagmin is a Ca2+ sensor that triggers exocytosis.