α₁β₂δ, a silent GABA_A receptor: Recruitment by tracazolate and neurosteroids

Background and purpose: This study investigated the α ₁β₂δ 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 α₁β₂δ 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 α₁β 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 (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.