A VERTEBRATE neurotoxin, α-latrotoxin, from black widow spider venom causes synaptic vesicle exocytosis and neurotransmitter release from presynaptic nerve terminals11-4. Although the mechanism of action of α-latrotoxin is not known, it does require binding of α-latrotoxin to a high-affinity receptor on the presynaptic plasma membrane5. The α-latrotoxin receptor seems to be exclusively at the presynaptic plasmamembrane6. Here we report that the α-latrotoxin receptor specifically binds to a synaptic vesicle protein, synaptotagmin, and modulates its phosphorylation. Synaptotagmin is a synaptic vesicle-specific membrane protein that binds negatively charged phospholipids and contains two copies of a putative Ca2+-binding domain from protein kinase C (the C2-domain), suggesting a regulatory role in synaptic vesicle fusion7,8. Our findings suggest that a physiological role of the α-latrotoxin receptor may be the docking of synaptic vesicles at the active zone. The direct interaction of the α-latrotoxin receptor with a synaptic vesicle protein also suggests a mechanism of action for this toxin in causing neurotransmitter release. © 1991 Nature Publishing Group.