title: MmTX1 and MmTX2 from coral snake venom potently modulate GABAA receptor activity.
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(+)/β(-) 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.
authors: Aix Marseille Université, CNRS, Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille UMR7286, 13344 Marseille, France;
authors: Jean-Pierre
authors: JP
authors: Rosso
authors: Institute of Molecular Neurogenetics, Zentrum für Molekulare Neurobiologie Hamburg, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany;
authors: Jürgen R
authors: JR
authors: Schwarz
authors: Lieber Institute for Brain Development, Johns Hopkins University School of Medicine, Baltimore, MD 21205;
authors: Marcelo
authors: M
authors: Diaz-Bustamante
authors: Aix Marseille Université, CNRS, Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille UMR7286, 13344 Marseille, France;
authors: Brigitte
authors: B
authors: Céard
authors: Instituto Clodomiro Picado, Facultad de Microbiología, Universidad de Costa Rica, 11501 San Jose, Costa Rica;
authors: José M
authors: JM
authors: Gutiérrez
authors: Institute of Molecular Neurogenetics, Zentrum für Molekulare Neurobiologie Hamburg, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany;
authors: Matthias
authors: M
authors: Kneussel
authors: Institut für Physiologie, Universität des Saarlandes, 66424 Homburg, Germany; and.
authors: Olaf
authors: O
authors: Pongs
authors: Department of Physiology and Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205 frankbosmans@jhmi.edu pierre-edouard.bougis@univ-amu.fr.
authors: Frank
authors: F
authors: Bosmans
authors: Aix Marseille Université, CNRS, Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille UMR7286, 13344 Marseille, France; frankbosmans@jhmi.edu pierre-edouard.bougis@univ-amu.fr.
authors: Pierre E
authors: PE
authors: Bougis
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004546:Elapid Venoms / Q000737:chemistry / Q000494:pharmacology*; D017815:Elapidae / Q000378:metabolism*; D057809:HEK293 Cells; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D007700:Kinetics; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009415:Nerve Net / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D011963:Receptors, GABA-A / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000494:pharmacology; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D014981:Xenopus
chemical_list: D004546:Elapid Venoms; D010455:Peptides; D021122:Protein Subunits; D011963:Receptors, GABA-A; D011994:Recombinant Proteins; C053972:micrurus venom
keywords: GABA(A) receptor; MmTX1; MmTX2; coral snake toxin; hippocampal neurons