Molecular analysis of neurotransmitter release.

The synaptic vesicle cycle can now be subdivided into a series of defined steps. These are the tethering of the SSV at the active site of the presynaptic membrane, followed by docking and by an ATP-dependent phase, termed priming. Fusion of the primed SSV with the plasma membrane is triggered by CA2+ entry through specific Ca2+ channels. All the steps in the SSV life cycle are regulated through a cascade of protein-protein and lipid-protein interactions. The SNARE proteins VAMP-2, SNAP-25 and syntaxin are essential for membrane fusion. Synaptotagmin is the major Ca2+ sensor for Ca(2+)-regulated exocytosis at the synapse. Rab3A and Rab3C regulate SSV neurotransmitter release by restricting exocytosis to a single vesicle per releasing site. The mobilization and the availability of SSVs are regulated by interactions with the actin cytoskeleton. Specific phospholipids, such as phosphoinositides, are essential in order to sustain both exocytosis and endocytosis.