The release of neurotransmitter into the synaptic cleft is triggered when an action potential reaches the axon terminal. This is followed by movement of vesicles to the presynaptic membrane, fusion of the vesicle membrane with the plasma membrane of the presynaptic terminal, and exocytosis of the vesicle contents into the synaptic cleft. The process by which vesicles move to the terminal for exocytosis of neurotransmitter involves a complex set of proteins, called SNARE proteins, that are present in the vesicle membrane, in the presynaptic terminal, and in the plasma membrane. The vesicle membrane proteins serve to dock the vesicle in place by forming complexes with similar SNARE proteins on the inner surface of the plasma membrane.
Some vesicles are docked at the terminal when the cell is at rest, but other vesicles are docked in response to incoming action potentials. The change in membrane voltage resulting from the action potential opens voltage-gated calcium channels in the presynaptic membrane, increasing calcium permeability and causing calcium influx into the terminal. This calcium is required for neurotransmitter release and is involved in initiating exocytosis of the vesicle contents. The precise mechanism by which an increase in intracellular calcium initiates the process of vesicle fusion is still unclear and is an active area of research. However, calcium is known to bind to a specific protein in the vesicle wall, named synaptotagmin, which mediates the final fusion of the vesicle and plasma membranes.