Synaptic transmission requires fusion between neurotransmitter-containing vesicles and the plasma membrane, a process that is mediated by members of the soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) family. SNAREs are membrane-associated proteins that share a common 60-70 amino acid motif in the cytosolic domain referred to as a SNARE motif. SNAREs on opposing membranes interact through SNARE motifs to form a highly stable four-helix bundle. Formation of the four-helix bundle brings the two opposing membranes in close proximity to one another and provides energy for membrane fusion. For synaptic transmission, an increase in intracellular calcium stimulates four-helix bundle formation and the subsequent release of neurotransmitters. A synaptic vesicle SNARE, VAMP-1 or VAMP-2 interacts with SNAP-25 and Syntaxin 1A on the plasma membrane to form a four-helix bundle, with SNAP-25 contributing two helices and VAMP-1 and Syntaxin 1A each contributing one helix. SNARE-associated proteins either facilitate SNARE complex formation or act as clamps to prevent four-helix bundle formation until an increase in intracellular calcium releases the clamping mechanism and enables membrane fusion.
Disruption of SNARE complex formation is detrimental to neurotransmission and is the primary mechanism of action of Botulinum neurotoxins. Botulinum neurotoxins, one of the most potent groups of human neurotoxins, proteolytically cleave SNAREs within motor neurons which inhibits Acetylcholine release and can lead to respiratory failure. Disruption of SNARE complex formation by a variety of mechanisms has also been implicated in the pathogenesis of neurodegenerative disorders, such as Parkinson's disease.