Neurexins are functional alpha-latrotoxin receptors.
Alpha-latrotoxin is a potent neurotoxin that triggers synaptic exocytosis. Surprisingly, two distinct neuronal receptors for alpha-latrotoxin have been described: CIRL/latrophilin 1 (CL1) and neurexin-1alpha. Alpha-latrotoxin is thought to trigger exocytosis by binding to CL1, while the role of neurexin 1alpha is uncertain. Using PC12 cells, we now demonstrate that neurexins indeed function as alpha-latrotoxin receptors that are at least as potent as CL1. Both alpha- and beta-neurexins represent autonomous alpha-latrotoxin receptors that are regulated by alternative splicing. Similar to CL1, truncated neurexins without intracellular sequences are fully active; therefore, neurexins and CL1 recruit alpha-latrotoxin but are not themselves involved in exocytosis. Thus, alpha-latrotoxin is unique among neurotoxins, because it utilizes two unrelated receptors, probably to amplify recruitment of alpha-latrotoxin to active sites.
Sugita
S
S
Department of Molecular Genetics, Howard Hughes Medical Institute, The University of Texas Southwestern Medical Center, Dallas 75235, USA.
Khvochtev
M
M
Südhof
T C
TC
D017398:Alternative Splicing; D000818:Animals; D001665:Binding Sites; D002118:Calcium / Q000502:physiology; D005089:Exocytosis / Q000502:physiology; D006023:Glycoproteins; D007074:Immunoglobulin G / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009479:Neuropeptides; D016716:PC12 Cells; D051381:Rats; D018000:Receptors, Peptide / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013111:Spider Venoms / Q000378:metabolism*; D014162:Transfection
D006023:Glycoproteins; D007074:Immunoglobulin G; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D018000:Receptors, Peptide; D011993:Recombinant Fusion Proteins; D013111:Spider Venoms; C034800:alpha-latrotoxin receptor; C112162:neurexophilin; C086959:neurexin Ibeta; C020763:alpha-latrotoxin; D002118:Calcium