BINDING OF SYNAPTOTAGMIN TO THE ALPHA-LATROTOXIN RECEPTOR IMPLICATES BOTH IN SYNAPTIC VESICLE EXOCYTOSIS

A VERTEBRATE neurotoxin, alpha-latrotoxin, from black widow spider venom causes synaptic vesicle exocytosis and neurotransmitter release from presynaptic nerve terminals 1-4. Although the mechanism of action of alpha-latrotoxin is not known, it does require binding of alpha-latrotoxin to a high-affinity receptor on the presynaptic plasma membrane 5. The alpha-latrotoxin receptor seems to be exclusively at the presynaptic plasmamembrane 6. Here we report that the alpha-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 fusion 7,8. Our findings suggest that a physiological role of the alpha-latrotoxin receptor may be the docking of synaptic vesicles at the active zone. The direct interaction of the alpha-latrotoxin receptor with a synaptic vesicle protein also suggests a mechanism of action for this toxin in causing neurotransmitter release.