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Vol. 273, Issue 3, 1705-1710, January 16, 1998

Neurexin Ialpha Is a Major alpha -Latrotoxin Receptor That Cooperates in alpha -Latrotoxin Action

Martin GeppertDagger §, Mikhail Khvotchev§, Valery Krasnoperov, Yukiko Godapar , Markus Missler§, Robert E. Hammer**, Konstantin Ichtchenko§, Alexander G. Petrenko, and Thomas C. Südhof§

From the Dagger  Max-Planck-Institut für Experimentelle Medizin, 37075 Göttingen, Germany, the Departments of § Molecular Genetics and ** Biochemistry, Howard Hughes Medical Institute, The University of Texas Southwestern Medical Center, Dallas, Texas 75235, the  Departments of Pharmacology, Physiology, and Neuroscience, New York University, New York, New York 10016, and the par  Department of Biology, University of California at San Diego, La Jolla, California 92093-0366

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 Ialpha binds alpha -latrotoxin in a Ca2+-dependent manner, and CIRL/latrophilin binds in a Ca2+-independent manner. We have now generated and analyzed mice that lack neurexin Ialpha 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 Ca2+-dependent alpha -latrotoxin binding sites. In cultured hippocampal neurons, alpha -latrotoxin was still capable of activating neurotransmission in the absence of neurexin Ialpha . 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 Ialpha 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 Ialpha pathway contributes to the Ca2+-dependent action of alpha -latrotoxin.

Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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