Abstract
Attenuated behavioral sensitivity to neurosteroids has been reported for mice deficient in the GABAA receptor δ subunit. We therefore investigated potential subunit-specific neurosteroid pharmacology of the following GABAA receptor isoforms in a transient expression system: α1β3γ2L, α1β3δ, α6β3γ2L, and α6β3δ. Potentiation of submaximal GABAA receptor currents by the neurosteroid tetrahydrodeoxycorticosterone (THDOC) was greatest for the α1β3δ isoform. Whole-cell GABA concentration–response curves performed with and without low concentrations (30 nm) of THDOC revealed enhanced peak GABAA receptor currents for isoforms tested without affecting the GABA EC50. α1β3δ currents were enhanced the most (>150%), whereas the other isoform currents were enhanced 15–50%. At a higher concentration (1 μm), THDOC decreased peak α1β3γ2L receptor current amplitude evoked by GABA (1 mm) concentration jumps and prolonged deactivation but had little effect on the rate or extent of apparent desensitization. Thus the polarity of THDOC modulation depended on GABA concentration for α1β3γ2L GABAA receptors. However, the same protocol applied to α1β3δ receptors resulted in peak current enhancement by THDOC of >800% and prolonged deactivation. Interestingly, THDOC induced pronounced desensitization in the minimally desensitizing α1β3δ receptors. Single channel recordings obtained from α1β3δ receptors indicated that THDOC increased the channel opening duration, including the introduction of an additional longer duration open state. Our results suggest that the GABAA receptor δ subunit confers increased sensitivity to neurosteroid modulation and that the intrinsic gating and desensitization kinetics of α1β3δ GABAA receptors are altered by THDOC.