MmTX1 and MmTX2 from coral snake venom potently modulate receptor activity modulate GABAa receptor activity

Jean Pierre Rosso, Jürgen R. Schwarz, Marcelo Diaz-Bustamante, Brigitte Céard, José M. Gutiérrez, Matthias Kneussel, Olaf Pongs, Frank Bosmans, Pierre E. Bougis

Research output: Contribution to journalArticle

Abstract

GABAA receptors shape synaptic transmission by modulating Cl- conductance across the cell membrane. Remarkably, animal toxins that specifically target GABAA receptors have not been identified. Here, we report the discovery of micrurotoxin1 (MmTX1) and MmTX2, two toxins present in Costa Rican coral snake venom that tightly bind to GABAA receptors at subnanomolar concentrations. Studies with recombinant and synthetic toxin variants on hippocampal neurons and cells expressing common receptor compositions suggest that MmTX1 and MmTX2 allosterically increase GABAA receptor susceptibility to agonist, thereby potentiating receptor opening as well as desensitization, possibly by interacting with the α+- interface. Moreover, hippocampal neuron excitability measurements reveal toxin-induced transitory network inhibition, followed by an increase in spontaneous activity. In concert, toxin injections into mouse brain result in reduced basal activity between intense seizures. Altogether, we characterized two animal toxins that enhance GABAA receptor sensitivity to agonist, thereby establishing a previously unidentified class of tools to study this receptor family.

Original languageEnglish (US)
Pages (from-to)E891-E900
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number8
DOIs
StatePublished - Feb 24 2015

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Keywords

  • Coral snake toxin
  • GABA(A) receptor
  • Hippocampal neurons
  • MmTX1
  • MmTX2

ASJC Scopus subject areas

  • General

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