alpha-Latrotoxin and its receptors: Neurexins and Cirl/latrophilins

alpha -Latrotoxin, a potent neurotoxin from black widow spider venom, trigg ers synaptic vesicle exocytosis from presynaptic nerve terminals. alpha -La trotoxin is a large protein toxin (120 kDa) that contains 22 ankyrin repeat s. In stimulating exocytosis, alpha -latrotoxin binds to two distinct famil ies of neuronal cell-surface receptors, neurexins and CLs (Cir1/latrophilin s), which probably have a physiological function in synaptic cell adhesion. Binding of alpha -latrotoxin to these receptors does not in itself trigger exocytosis but serves to recruit the toxin to the synapse. Receptor-bound alpha -latrotoxin then inserts into the presynaptic plasma membrane to stim ulate exocytosis by two distinct transmitter-specific mechanisms. Exocytosi s of classical neurotransmitters (glutamate, GABA, acetylcholine) is induce d in a calcium-independent manner by a direct intracellular action of alpha -latrotoxin, while exocytosis of catecholamines requires extracellular cal cium. Elucidation of precisely how alpha -latrotoxin works is likely to pro vide major insight into how synaptic vesicle exocytosis is regulated, and h ow the release machineries of classical and catecholaminergic neurotransmit ters differ.