Enhanced Neurosteroid Potentiation of Ternary GABAA Receptors Containing the Subunit

Attenuated behavioral sensitivity to neurosteroids has been reported for mice deficient in the GABAA receptor subunit. We therefore investigated potential subunit-specific neurosteroid pharmacology of the following GABAA receptor isoforms in a transient expression system: 1 3 2L, 1 3 , 6 3 2L, and 6 3 . Potentiation of submaximal GABAA receptor currents by the neurosteroid tetrahydrodeoxycorticosterone (THDOC) was greatest for the 1 3 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. 1 3 currents were enhanced the most ( 150%), whereas the other isoform currents were enhanced 15–50%. At a higher concentration (1 M), THDOC decreased peak 1 3 2L 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 1 3 2L GABAA receptors. However, the same protocol applied to 1 3 receptors resulted in peak current enhancement by THDOC of 800% and prolonged deactivation. Interestingly, THDOC induced pronounced desensitization in the minimally desensitizing 1 3 receptors. Single channel recordings obtained from 1 3 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 subunit confers increased sensitivity to neurosteroid modulation and that the intrinsic gating and desensitization kinetics of 1 3 GABAA receptors are altered by THDOC.