NEUREXIN I-ALPHA IS A MAJOR ALPHA-LATRATOXIN RECEPTOR THAT COOPERATESIN ALPHA-LATROTOXIN ACTION

alpha-Latrotoxin is a potent neurotoxin from black widow spider venom that binds to presynaptic receptors and causes massive neurotransmitte r release. A surprising finding was the biochemical description of two distinct cell surface proteins that bind alpha-latrotoxin with nanomo lar affinities; Neurexin I alpha binds alpha-latrotoxin in a Ca2+- dep endent manner, and CIRL/latrophilin binds in a Ca2+-independent manner . We have now generated and analyzed mice that lack neurexin I alpha t o test its importance in alpha-latrotoxin action, alpha-Latrotoxin bin ding to brain membranes from mutant mice was decreased by almost 50% c ompared with wild type membranes; the decrease was almost entirely due to a loss of Ca2+-dependent alpha-latrotoxin binding sites. In cultur ed hippocampal neurons, alpha-latrotoxin was still capable of activati ng neurotransmission in the absence of neurexin I alpha. Direct measur ements of [H-3]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 al pha-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 affinit ies and abundance but different properties and functions. The action o f alpha-latrotoxin may therefore be mediated by independent parallel p athways, of which the CIRL/latrophilin pathway is sufficient for neuro transmitter release, whereas the neurexin I alpha pathway contributes to the Ca2+-dependent action of alpha-latrotoxin.