A sequential view of neurotransmitter release.

Only a few years ago it was thought that a single Ca2+-dependent membrane binding protein might control regulated exocytosis, but it is now clear that the coordinated actions of a large number of proteins and lipids are required for the precise targeting, docking and fusion of vesicles to the plasma membrane. Thinking was focused in 1993 by the SNARE (soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor) hypothesis, which proposed that certain synaptic vesicle membrane proteins combined specifically with particular proteins in the synaptic membrane active zone to form a complex that interacted with synaptoplasmic proteins, ATP and calcium ions to fuse the vesicles with the presynaptic membrane. Much research that has followed has verified the basic predictions of the SNARE hypothesis. However, recent research indicates that SNARE proteins are more widely distributed in secretory systems and that the sequence in which the proteins function may not occur as was originally proposed. That has recently produced a period of deconstruction and reinterpretation of the SNARE hypothesis. Our present state of knowledge is briefly summarized in this review.