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. 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. The alpha-latrotoxin receptor seems to be exclusively at the presynaptic plasmamembrane. 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 Ca(2+)-binding domain from protein kinase C (the C2-domain), suggesting a regulatory role in synaptic vesicle fusion. 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.
Petrenko
A G
AG
Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75235.
Perin
M S
MS
Davletov
B A
BA
Ushkaryov
Y A
YA
Geppert
M
M
Südhof
T C
TC
D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000648:ultrastructure; D001923:Brain Chemistry; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins; D002417:Cattle; D005089:Exocytosis; D008562:Membrane Glycoproteins / Q000302:isolation & purification / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000302:isolation & purification / Q000378:metabolism*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D011950:Receptors, Cholinergic / Q000302:isolation & purification / Q000378:metabolism*; D018000:Receptors, Peptide; D013111:Spider Venoms; D013572:Synaptic Vesicles / Q000378:metabolism*; D050857:Synaptotagmins
D002135:Calcium-Binding Proteins; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D011950:Receptors, Cholinergic; D018000:Receptors, Peptide; D013111:Spider Venoms; C034800:alpha-latrotoxin receptor; D050857:Synaptotagmins; D011493:Protein Kinase C; D002118:Calcium