Neurotransmitters are secreted rapidly after stimulation because synaptic vesicles wait at the presynapse with their membrane fusion machinery already part-assembled, say Walter et al.
Synaptic vesicles dock at the plasma membrane and become “primed” for quick release in response to increased calcium levels. The release stage is controlled by SNARE proteins in both the vesicle and presynaptic membranes, which assemble into a complex that promotes membrane fusion. Whether the vesicle SNARE synaptobrevin only binds its target membrane partners at the fusion step or whether it binds earlier during vesicle priming is unclear.
Walter et al. mutated synaptobrevin's SNARE-interaction domain and measured the protein's ability to support vesicle priming and fusion in neuroendocrine cells. Mutations at the N-terminal end that destabilized synaptobrevin's interaction with its SNARE partners lowered the number of primed vesicles. But the vesicles that remained were still secreted as quickly as they were in cells expressing wild-type synaptobrevin. In contrast, mutations in the C-terminal end of synaptobrevin's binding motif slowed the speed with which vesicles were released.
The researchers think that the interaction domains of synaptobrevin and the other SNARE proteins come together at their N termini to prime vesicles for release and pause in this intermediate state before calcium causes them to zip their C termini into a fully assembled SNARE complex driving membrane fusion. Once they are primed, synaptic vesicles might be committed to release, so senior author Jakob Sørensen now wants to investigate how the priming step is regulated.