Unique insecticide specificity of human homomeric ρ1 GABAC receptor

Gurpreet S. Ratra, Brian E. Erkkila, David S. Weiss, John E. Casida

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

Several convulsants and major insecticides block the γ-aminobutyric acid (GABA)-gated chloride channel in brain on binding to the GABAA receptor. The GABAC receptor, important in retina and present in brain, is also coupled to a chloride channel and is therefore a potential target for toxicant action examined here in radioligand binding and electrophysiological experiments. Human homomeric ρ1 GABAC receptor expressed in human embryonic kidney cells (HEK293) undergoes specific and saturable high-affinity binding of 4-n-[3H]propyl-4′-ethynylbicycloorthobenzoate ([3H]EBOB) using a cyano analog (CNBOB) to determine non-specific binding. This GABAC ρ1 receptor is very sensitive to CNBOB and lindane relative to α-endosulfan, tert-butylbicyclophosphorothionate, picrotoxinin and fipronil (IC50 values of 23, 91, 800, 1080, 4000 and > 10000 nM, respectively, in displacing [3H]EBOB). A similar potency sequence (except for picrotoxinin) is observed for inhibition of GABA-induced currents of ρ1 receptor expressed in Xenopus oocytes. The present study does not consider ρ2 homomeric and ρ1ρ2 heteromeric GABAC receptors which are known to be more sensitive than ρ1 to picrotoxinin. The inhibitor sensitivity and specificity of this ρ1 GABAC receptor differ greatly from those of human homomeric β3 and native GABAA receptors.

Original languageEnglish (US)
Pages (from-to)47-53
Number of pages7
JournalToxicology Letters
Volume129
Issue number1-2
DOIs
StatePublished - Mar 24 2002
Externally publishedYes

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Keywords

  • Binding site specificity
  • GABA ρ1 receptor
  • GABA-induced currents
  • Insecticide
  • [H]EBOB
  • γ-Aminobutyric acid

ASJC Scopus subject areas

  • Toxicology

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