Background and purpose: This study investigated the α 1β2δ isoform of the GABAA receptor that is presumably expressed in the forebrain. The functional and pharmacological properties of this receptor combination are largely unknown. Experimental approach: We expressed α1β2δ GABAA 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 α1β 2δ isoform of the GABAA receptor exhibited an extremely small GABA-mediated current. Tracazolate increased the current amplitude evoked by a half-maximal concentration (EC50) 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 EC50. 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 EC50 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, α1β2δ 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.
- Neurosteroid THDOC
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