The pharmacology of spontaneously open α1β3ε GABAA receptor-ionophores

Gábor Maksay, Sally A. Thompson, Keith A. Wafford

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

Human α1β3ε GABAA receptors were expressed in Xenopus oocytes and examined using the conventional two-electrode voltage-clamp technique and compared to α1β3γ2 receptors. The effects of several GABAA agonists were studied, and the allosteric modulation of the channel by a number of GABAergic modulators investigated. The presence of the ε subunit increased the potency and efficacy of direct activation by partial GABAA agonists (piperidine-4-sulphonic acid and thio-4-PIOL), pentobarbital and neurosteroids. Direct activation by 3-hydroxylated neurosteroids was restricted to 3α epimers, while chirality at C5 was indifferent. The 3β-sulfate esters of pregnenolone and dehydroepiandrosterone inhibited the spontaneous currents with efficacies higher, while bicuculline methiodide and SR 95531 did so lower than picrotoxin and TBPS. Furosemide, fipronil, triphenylcyanoborate and Zn2+ blocked the spontaneous currents of α1β3ε receptors with different efficacies. Flunitrazepam and 4′-chlorodiazepam inhibited the spontaneous currents with micromolar potencies. In conclusion, spontaneously active α1β3ε GABAA receptors can be potentiated and blocked by GABAergic agents within a broad range of efficacy.

Original languageEnglish
Pages (from-to)994-1002
Number of pages9
JournalNeuropharmacology
Volume44
Issue number8
DOIs
Publication statusPublished - Jun 2003

Keywords

  • GABA antagonists
  • GABA partial agonists
  • GABA receptor-ionophore complex
  • Neurosteroids
  • Spontaneous activity

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

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