Specialized proteins which are involved in neurotransmitter release have been identified on the vesicle membrane and the pre-synaptic membrane, as well as within the cytoplasm. The many proteins are thought to be involved in keeping the vesicles in place, sensing calcium influx, guiding the vesicles to active zones, docking vesicles at the pre-synaptic membrane, and in allowing fusion and exocytosis to occur. The exact role of the identified proteins continues to be a major topic in neuroscience.
VAMP's (vesicle membrane proteins) are involved in holding vesicles in place, sensing Ca++ influx, and in the initial phases of exocytosis. The synapsin group, a family of four proteins of which synapsin I and synapsin II are the best studied, have been identified on the vesicle membrane and are thought to play a role in holding vesicles in place. Rab3a and Rab3b, two members of a class of proteins that bind GTP, are thought to be involved in guiding mobile vesicles to active zones where docking occurs. Synaptobrevin, another VAMP, is a protein that may be involved in recognition of the plasma membrane.
Two other well studied proteins associated with the vesicle membrane are synaptotagmin and synaptophysin. Synaptotagmin, with a membrane spanning region, has a Ca++ binding domain and, in the presence of Ca++, binds phospholipids. It is thought to play a role in sensing Ca++ influx and starting the process of vesicle fusion. Synaptophysin, of which there are about 10-20 copies per vesicle, may be involved in forming a fusion pore with the pre-synaptic membrane.
Proteins have also been identified on the presynaptic membrane which are necessary for neurotransmitter release. Syntaxin, a membrane spanning protein, may be involved in recognizing the vesicle membrane. SNAP-25 (no relation to cytoplasmic SNAP's) attaches to the plasma membrane through fatty acid groups and acts as a SNARE (SNAP receptor protein) in vesicle docking. Another protein on the presynaptic membrane, physophilin, may be involved in forming a fusion pore. In vitro, physophilin and synaptophysin join to form a pore.
Finally, there are two sets of cytoplasmic proteins involved in vesicle docking. The N-ethylmaleimide sensitive fusion protein (NSF) is one group and the second is called the soluble NSF attachment proteins (SNAP). In the fusion of synaptic vesicles to the pre-synaptic membrane, these general cytoplasmic proteins are thought to intervene between two specific proteins, one on the vesicle and one of the pre-synaptic membrane, to create a fusion pore.