α 1β 2δ, a silent GABA A receptor: Recruitment by tracazolate and neurosteroids

N. Zheleznova, A. Sedelnikova, D. S. Weiss

Research output: Contribution to journalArticle

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Abstract

Background and purpose: This study investigated the α 1β 2δ isoform of the GABA A receptor that is presumably expressed in the forebrain. The functional and pharmacological properties of this receptor combination are largely unknown. Experimental approach: We expressed α 1β 2δ GABA A receptors in Xenopus laevis oocytes. GABA-activated currents, in the presence and absence of modulators, were recorded using the two-electrode voltage clamp technique. Key results: The α 1β 2δ isoform of the GABA A receptor exhibited an extremely small GABA-mediated current. Tracazolate increased the current amplitude evoked by a half-maximal concentration (EC 50) of GABA by 59-fold. The maximum current was increased 23-fold in the presence of a saturating GABA concentration. Concomitant with the increase in the maximum, was a 4-fold decrease in the EC 50. Finally, a mutation in the second transmembrane domain of the δ subunit that increases receptor efficacy (L286S), eliminated the increase in the maximum GABA-activated current. The endogenous neurosteroid, tetrahydrodeoxycorticosterone (THDOC), also decreased the EC 50 and increased the maximum current amplitude, although to a lesser degree than that of tracazolate. Conclusions and implications: Taken all together, these findings indicate that the small GABA-mediated currents in the absence of the modulator are due to a low efficacy for activation. In the absence of modulators, α 1β 2δ GABA receptors would be effectively silent and therefore contribute little to inhibition in the CNS. In the presence of tracazolate or endogenous neurosteroids however, this particular receptor isoform could exert a profound inhibitory influence on neuronal activity.

Original languageEnglish (US)
Pages (from-to)1062-1071
Number of pages10
JournalBritish Journal of Pharmacology
Volume153
Issue number5
DOIs
Publication statusPublished - Mar 1 2008

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Keywords

  • Neurosteroid THDOC
  • Tracazolate
  • α β δ GABA receptors

ASJC Scopus subject areas

  • Pharmacology

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