Neurexin Iα is a major α-latrotoxin receptor that cooperates in α- latrotoxin action

Martin Geppert, Mikhail Khvotchev, Valery Krasnoperov, Yukiko Goda, Markus Missler, Robert E Hammer, Konstantin Ichtchenko, Alexander G. Petrenko, Thomas C. Südhof

Research output: Contribution to journalArticlepeer-review

83 Scopus citations

Abstract

α-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 α-latrotoxin with nanomolar affinities; Neurexin Iα binds α-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 Iα tot est its importance in α-latrotoxin action. α- 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 α-latrotoxin binding sites. In cultured hippocampal neurons, α-latrotoxin was still capable of activating neurotransmission in the absence of neurexin Iα. Direct measurements of [3H] glutamate release from synaptosomes, however, showed a major decrease in the amount of release triggered by α-latrotoxin in the presence of Ca2+. Thus neurexin Iα is not essential for α-latrotoxin action but contributes to α-latrotoxin action when Ca2+ is present. Viewed as a whole, our results show that mice contain two distinct types of α-latrotoxin receptors with similar affinities and abundance but different properties and functions. The action of α-latrotoxin may therefore be mediated by independent parallel pathways, of which the CIRL/latrophilin pathway is sufficient for neurotransmitter release, whereas the neurexin Iα pathway contributes to the Ca2+-dependent action of α-latrotoxin.

Original languageEnglish (US)
Pages (from-to)1705-1710
Number of pages6
JournalJournal of Biological Chemistry
Volume273
Issue number3
DOIs
StatePublished - Jan 16 1998

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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