Complexin (also known as synaphin) refers to a one of a small set of eukaryotic cytoplasmic neuronal proteins which binds to the SNARE protein complex (SNAREpin) with a high affinity. These are called synaphin 1 and 2. In the presence of Ca2+, the transport vesicle protein synaptotagmin displaces complexin, allowing the SNARE protein complex to bind the transport vesicle to the presynaptic membrane. Complexin acts as both an inhibitor and a facilitator of synaptic vesicle fusion and neurotransmitter release. In one conformation, it clamps SNAREpin complexes, preventing vesicle fusion, while in a different conformation it releases the SNAREpins, allowing synaptotagmin to trigger fusion. Whereas complexin is not necessary for synaptic vesicle exocytosis, it does increase neurotransmitter release by 60–70% as demonstrated by complexin gene knockout in mice. A number of human neurological diseases have been linked to a deficiency of complexin. Synaphin can promote exocytosis by promoting interaction between the complementary syntaxin and synaptobrevin transmembrane regions that reside in opposing membranes prior to fusion. Structure and Binding Complexin is a small highly charged cytosolic protein that is hydrophilic, rich in glutamic acid and lysine residues. Complexin's central region (amino acids 48–70) binds to the SNARE core as an anti-parallel α-helix, which attaches complexin to the SNARE complex. It interacts selectively with the ternary SNARE complex but not with monomeric SNARE proteins. Complexin binds to the groove between the synaptobrevin and syntaxin helices. Complexin stabilizes the C-terminal part of the SNARE complex. Function Complexin acts as a positive regulator of synaptic vesicle exocytosis, and binds selectively to the neuronal SNARE complex. Complexin has a two-fold function in that it can act as either a promoter or an inhibitor of vesicle fusion. This dual-functionality is dependent upon synaptic activity such as a depolarizing stimulus arriving at the synapse. By acting as a fusion clamp in inhibiting fusion, and a promoter during depolarization, complexin concentration levels regulate vesicle pool size such as that of the ready releasable pool, important for short term response changes. Complexin Acts to Inhibit Fusion - Fusion Clamping Inhibition of fusion is necessary to prevent spontaneous exocytosis of vesicles into the synapse. If a clamp does not hold synaptic vesicle pools stable and inhibit them from fusing, the potential for spontaneous firing and depletion of the vesicle pool is much greater. It is believed that the C-terminal domain of complexin is responsible for this inhibitory function. In several eukaryotic