Core proteins of the secretory machinery

Members of the Rab, SM- and SNARE-protein families play key roles in all intracellular membrane trafficking steps. While SM- and SNARE-proteins become directly involved in the fusion reaction at a late stage, Rabs and their effectors mediate upstream steps such as vesicle budding, delivery, tethering, and transport. Exocytosis of synaptic vesicles and regulated secretory granules are among the best-studied fusion events and involve the Rab3 isoforms Rab3A-D, the SM protein munc18-1, and the SNAREs syntaxin 1A, SNAP-25, and synaptobrevin 2. According to the current view, syntaxin 1A and SNAP-25 at the presynaptic membrane form a complex with synaptic vesicle-associated synaptobrevin 2. As complex formation proceeds, the opposed membranes are pulled tightly together, enforcing the fusion reaction. Munc18-1 is essential for regulated exocytosis and interacts with syntaxin 1A alone or with SNARE complexes, suggesting a role for munc18-1 in controlling the SNARE-assembly reaction. Compared to other intracellular fusion steps, special adaptations evolved in the synapse to allow for the tight regulation and high membrane turnover rates required for synaptic transmission. Synaptic vesicle fusion is triggered by the intracellular second messenger calcium, with members of the synaptotagmin protein family being prime candidates for linking calcium influx to fusion in the fast phase of exocytosis. To compensate for the massive incorporation of synaptic vesicles into the plasma membrane during exocytosis, special adaptations to endocytic mechanisms have evolved at the synapse to allow for efficient vesicle recycling.