RAB3 and synaptotagmin: the yin and yang of synaptic membrane fusion

Synaptic vesicle exocytosis occurs in consecutive steps: docking, which specifically attaches vesicles to the active zone; priming, which makes the vesicles competent for Ca(2+)-triggered release and may involve a partial fusion reaction; and the final Ca(2+)-regulated step that completes fusion. Recent evidence suggests that the critical regulation of the last step in the reaction is mediated by two proteins with opposite actions: synaptotagmin, a Ca(2+)-binding protein that is essential for Ca(2+)-triggered release and probably serves as the Ca(2+)-sensor in fusion, and rab3, which limits the number of vesicles that can be fused as a function of Ca2+ in order to allow a temporally limited, repeatable signal.