Membrane fusion is a critical process for vesicle trafficking and intercellular communication in eukaryotes. Fusion of lipid bilayers is an endothermic reaction. It requires specialized proteins to bring two membranes in close proximity to overcome electrostatic forces derived from charged lipid head groups. Once the membranes are in close proximity, the boundary between hydrophilic and hydrophobic parts of the bilayer has to be destabilized. This destabilization may either lead to a complete merger of the two bilayers forming a fusion pore or may result in a hemifusion intermediate before complete opening of a fusion pore (61) (Fig. 1). Synaptic transmission requires fusion of neurotransmitter filled synaptic vesicles with the plasma membrane. Synaptic vesicle fusion is typically driven by the Ca2+ influx triggered by action potential mediated depolarization of a presynaptic nerve terminal. Transmitter release is restricted to a specialized region on the nerve terminal known as the active zone, which can be easily identified in electron micrographs due to its high electron density. Synaptic vesicles dock at the active zone in the vicinity of voltage gated Ca2+ channels and upon action potential arrival, Ca2+ influx through these channels drive vesicle fusion with a time course of less than 100 microseconds (69). In addition, synaptic vesicles can also fuse spontaneously albeit at a very low probability (~1 vesicle per minute per active zone) (29, 52). The last two decades have witnessed major leaps in our understanding of the mechanisms underlying neurotransmitter release (43, 66, 67, 83). These studies have identified several molecular components of the synaptic vesicle fusion machinery that are critical for neurotransmission. A core group of these proteins are called SNAREs (acronym for soluble N-ethylmaleimide-sensitive factor attachment protein.
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