Synaptotagmin 1 directs repetitive release by coupling vesicle exocytosis to the Rab3 cycle.

Neurons communicate with one another at junctions called synapses. The arrival of an electrical signal called an action potential causes calcium ions to enter the first cell, which in turn triggers the release of molecules called neurotransmitters into the gap between the neurons. The binding of these molecules to receptors on the second cell then enables the action potential to be regenerated. For cells to respond rapidly and reliably to incoming electrical signals, they must maintain a supply of vesicles—the packages that contain neurotransmitters—close to the site where they are released from the first cell. The vesicles are held in contact with the cell membrane by a structure called the docking complex. A number of the proteins in this docking complex have been identified, including two that have been referred to as the ‘yin and yang’ of vesicle fusion: synaptotagmin, which promotes fusion, and Rab3, which limits it. However, little is known about how these and other proteins interact to keep vesicles docked at the membrane. Cheng, Wang et al. have now clarified the docking process with the aid of experiments in nematode worms. In resting neurons that are not releasing neurotransmitters, synaptotagmin (‘yin’) binds to an enzyme called GAP and prevents it from converting GTP—an energy-storage molecule—into GDP. Given that Rab3 (‘yang’) requires a molecule of GTP to power its own activity, the actions of synaptotagmin ensure that Rab3 has enough energy to remain bound to other proteins within the docking complex. However, when an action potential arrives, calcium ions enter the neuron, and some of them bind to synaptotagmin. This disrupts its interaction with the GAP enzyme, which thus becomes free to convert the GTP molecule bound to Rab3 into GDP. The loss of its energy source causes Rab3 to separate from its binding partners, and docking complex collapses. As a result, vesicles fuse with the membrane and release neurotransmitter molecules into the synapse. Given that Rab3 and synaptotagmin have changed little over the course of evolution, it is highly likely that the same indirect interaction between these two proteins also regulates the release of transmitter at synapses in the mammalian brain.