SNAREs and regulated vesicle exocytosis

Synaptic vesicle exocytosis—the basis for neurotransmitter release at nerve terminals—is at the heart of nervous system functioning. The molecular analysis of this special form of exocytosis was recently greatly stimulated by the finding that the key molecules in various intracellular vesicular transport steps, including neurotransmitter release, are conserved from yeast to man (1–3). Prompted by this generality of vesicular transport machinery Rothman and colleagues proposed a universal “docking and fusion particle” to explain vesicle docking and fusion at all locations, including synapses (4). The Rothman proposal, also called the SNARE hypothesis, identifies four key components: ( i ) a v esicle membrane protein named v-SNARE, ( ii ) a t arget membrane protein dubbed t-SNARE, ( iii ) a cytosolic protein required for membrane fusion N -ethylmaleimide-sensitive fusion protein (NSF), and ( iv ) adaptors for NSF termed SNAPs (soluble NSF attachment proteins) (Fig. 1 a ). Vesicle docking is accounted for by the complementarity between the v- and t-SNAREs. The assembled v- and t-SNARE then acts as a receptor for the SNAPs, which in turn incorporates the fusion protein, NSF. The docking and fusion particle containing all four basic parts, thus formed, is called the SNARE complex. In this scheme, vesicle fusion is achieved by the energy liberated from the hydrolysis of ATP by NSF, which is an ATPase. By virtue of its simplicity the SNARE hypothesis has gained popularity and become a familiar term for those drawn to the intricacies of intracellular membrane traffic. The popularity, however, has also attracted intense scientific scrutiny to the SNARE hypothesis from every imaginable angle. This commentary provides a brief perspective on the docking and fusion particle as it applies to synapse function and places recent findings (5, 6) in context. ( a ) Schematic diagram indicating four essential components of the docking and fusion particle, also called the SNARE …