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Involvement of the GABAA receptor α subunit in the mode of action of etifoxine.
Mattei, César; Taly, Antoine; Soualah, Zineb; Saulais, Ophélie; Henrion, Daniel; Guérineau, Nathalie C; Verleye, Marc; Legros, Christian.
Afiliação
  • Mattei C; Institut MITOVASC, UMR CNRS 6015 - UMR INSERM U1083, Université d'Angers, 3 Rue Roger Amsler 49100 ANGERS, France. Electronic address: cesar.mattei@univ-angers.fr.
  • Taly A; Theoretical Biochemistry Laboratory, Institute of Physico-Chemical Biology, CNRS UPR9080, University of Paris Diderot Sorbonne Paris Cité, 75005 Paris, France.
  • Soualah Z; Institut MITOVASC, UMR CNRS 6015 - UMR INSERM U1083, Université d'Angers, 3 Rue Roger Amsler 49100 ANGERS, France.
  • Saulais O; Institut MITOVASC, UMR CNRS 6015 - UMR INSERM U1083, Université d'Angers, 3 Rue Roger Amsler 49100 ANGERS, France.
  • Henrion D; Institut MITOVASC, UMR CNRS 6015 - UMR INSERM U1083, Université d'Angers, 3 Rue Roger Amsler 49100 ANGERS, France.
  • Guérineau NC; Institut MITOVASC, UMR CNRS 6015 - UMR INSERM U1083, Université d'Angers, 3 Rue Roger Amsler 49100 ANGERS, France.
  • Verleye M; Biocodex, Department of Pharmacology, Zac de Mercières, 60200 Compiègne, France.
  • Legros C; Institut MITOVASC, UMR CNRS 6015 - UMR INSERM U1083, Université d'Angers, 3 Rue Roger Amsler 49100 ANGERS, France. Electronic address: christian.legros@univ-angers.fr.
Pharmacol Res ; 145: 104250, 2019 07.
Article em En | MEDLINE | ID: mdl-31059790
ABSTRACT
Etifoxine (EFX) is a non-benzodiazepine psychoactive drug which exhibits anxiolytic effects through a dual mechanism, by directly binding to GABAA receptors (GABAARs) and to the mitochondrial 18-kDa translocator protein, resulting in the potentiation of the GABAergic function. The ß subunit subtype plays a key role in the EFX-GABAAR interaction, however this does not explain the anxiolytic effects of this drug. Here, we combined behavioral and electrophysiological experiments to challenge the role of the GABAAR α subunit in the EFX mode of action. After single administrations of anxiolytic doses (25-50 mg/kg, intraperitoneal), EFX did not induce any neurological nor locomotor impairments, unlike the benzodiazepine bromazepam (0.5-1 mg/kg, intraperitoneal). We established the EFX pharmacological profile on heteropentameric GABAARs constructed with α1 to α6 subunit expressed in Xenopus oocyte. Unlike what is known for benzodiazepines, neither the γ nor δ subunits influenced EFX-mediated potentiation of GABA-evoked currents. EFX acted first as a partial agonist on α2ß3γ2S, α3ß3γ2S, α6ß3γ2S and α6ß3δ GABAARs, but not on α1ß3γ2S, α4ß3γ2S, α4ß3δ nor α5ß3γ2S GABAARs. Moreover, EFX exhibited much higher positive allosteric modulation towards α2ß3γ2S, α3ß3γ2S and α6ß3γ2S than for α1ß3γ2S, α4ß3γ2S and α5ß3γ2S GABAARs. At 20 µM, corresponding to brain concentration at anxiolytic doses, EFX increased GABA potency to the highest extent for α3ß3γ2S GABAARs. We built a docking model of EFX on α3ß3γ2S GABAARs, which is consistent with a binding site located between α and ß subunits in the extracellular domain. In conclusion, EFX preferentially potentiates α2ß3γ2S and α3ß3γ2S GABAARs, which might support its advantageous anxiolytic/sedative balance.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Oxazinas / Ansiolíticos / Receptores de GABA-A / Subunidades Proteicas Limite: Animals Idioma: En Ano de publicação: 2019 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Oxazinas / Ansiolíticos / Receptores de GABA-A / Subunidades Proteicas Limite: Animals Idioma: En Ano de publicação: 2019 Tipo de documento: Article