Experiments in C. elegans reveal how synaptotagmin and Rab3, the 'yin and yang' of synapses, control whether transmitter vesicles remain docked at the presynaptic membrane or release their contents into the synapse.
Synaptotagmin-7 acts synergistically with synaptotagmin-1 by placing vesicles close to the plasma membrane within reach of the SNARE/Munc13-complex, supporting their priming and setting the stage for fast and slow fusion.
Drosophila synaptotagmin 7 functions to restrict SV availability and release, but does not act as the Ca2+ sensor mediating the asynchronous release and facilitation remaining in synaptotagmin 1 mutants.
Cooperative action of synaptotagmin and complexin is needed to arrest all SNARE complexes on a vesicle, and the reversal of the synaptotagmin clamp is sufficient to achieve fast, Ca2+-synchronized fusion.
A model for synchronous neurotransmitter release suggests that when not in the presence of calcium ions, Synaptotagmin proteins form ring-like structures between the vesicle and plasma membrane that prevent spontaneous fusion.