Neurexin I alpha is a major alpha-latrotoxin receptor that cooperates in alpha-latrotoxin action.
alpha-Latrotoxin is a potent neurotoxin from black widow spider venom that binds to presynaptic receptors and causes massive neurotransmitter release. A surprising finding was the biochemical description of two distinct cell surface proteins that bind alpha-latrotoxin with nanomolar affinities; Neurexin I alpha binds alpha-latrotoxin in a Ca(2+)-dependent manner, and CIRL/latrophilin binds in a Ca(2+)-independent manner. We have now generated and analyzed mice that lack neurexin I alpha to test its importance in alpha-latrotoxin action. alpha-Latrotoxin binding to brain membranes from mutant mice was decreased by almost 50% compared with wild type membranes; the decrease was almost entirely due to a loss of Ca(2+)-dependent alpha-latrotoxin binding sites. In cultured hippocampal neurons, alpha-latrotoxin was still capable of activating neurotransmission in the absence of neurexin I alpha. Direct measurements of [3H]glutamate release from synaptosomes, however, showed a major decrease in the amount of release triggered by alpha-latrotoxin in the presence of Ca2+. Thus neurexin I alpha is not essential for alpha-latrotoxin action but contributes to alpha-latrotoxin action when Ca2+ is present. Viewed as a whole, our results show that mice contain two distinct types of alpha-latrotoxin receptors with similar affinities and abundance but different properties and functions. The action of alpha-latrotoxin may therefore be mediated by independent parallel pathways, of which the CIRL/latrophilin pathway is sufficient for neurotransmitter release, whereas the neurexin I alpha pathway contributes to the Ca(2+)-dependent action of alpha-latrotoxin.
Geppert
M
M
Max-Planck-Institut für Experimentelle Medizin, Göttingen, Germany.
Khvotchev
M
M
Krasnoperov
V
V
Goda
Y
Y
Missler
M
M
Hammer
R E
RE
Ichtchenko
K
K
Petrenko
A G
AG
Südhof
T C
TC
D017398:Alternative Splicing; D000818:Animals; D001921:Brain / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002874:Chromosome Mapping; D018698:Glutamic Acid / Q000378:metabolism; D006023:Glycoproteins; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009479:Neuropeptides; D018000:Receptors, Peptide / Q000235:genetics / Q000378:metabolism*; D013111:Spider Venoms / Q000235:genetics / Q000378:metabolism*; D009435:Synaptic Transmission; D013574:Synaptosomes / Q000378:metabolism
D006023:Glycoproteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D018000:Receptors, Peptide; D013111:Spider Venoms; C034800:alpha-latrotoxin receptor; C112162:neurexophilin; D018698:Glutamic Acid; C020763:alpha-latrotoxin; D002118:Calcium