Data versus Dogma: New Challenges for SNARE-based Models of “Fast” Exocytosis at Nerve Terminals

Abstract

Over the last several years, progress in understanding the molecular mechanism of fast, Ca²⁺-dependent exocytosis at nerve terminals has led to the following textbook picture:

The depolarization-dependent opening of presynaptic Ca²⁺ channels leads to a transient elevation of cytosolic Ca ion activity within the vicinity of docked synaptic vesicles. The binding of Ca²⁺ to synaptotagmin 1 (or, 2) then initiates a poorly understood reaction that allows vesicular and target SNAREs (soluble,N-ethylmaleimide-sensitivefactorattachment protein receptors) to complete their intermolecular coiling. The energy released by SNARE coiling then drives fusion between the membrane of suitably primed vesicles and the plasma membrane. Although there is widespread agreement that SNAREs and synaptotagmin are crucial for the molecular events that culminate in fast, synchronous exocytosis at neuronal synapses, there remains no consensus about how these proteins trigger the membrane fusion event that is central to this process. This review extends earlier criticisms of models implicating SNAREs in the terminal steps of the exocytotic cascade and explains how recent data are more compatible with a direct role for synaptotagmin 1 (or, 2) in this process.