Direct channel-gating and modulatory effects of triiodothyronine on recombinant GABA(A) receptors.

We have previously shown that triiodothyronine (T3) inhibits gamma-aminobutyric acid type A (GABA(A)) receptors in synaptoneurosomes and transfected cells. To further characterize this phenomenon, the effect of T3 on recombinant GABA(A) receptors expressed in Xenopus oocytes was investigated using the two-electrode voltage-clamp method. T3 inhibited GABA-gated chloride currents in a non-competitive manner and yielded an IC50 of 7.3 +/- 0.8 microM in oocytes coexpressing alpha1beta2gamma2L receptor subunits. T3 had no inhibitory effect on alpha6beta2gamma2L or beta2gamma2L receptor constructs, indicating that the alpha1 subunit imparts T3 sensitivity to the receptor. In addition to the inhibitory effect of T3 on GABA responses, T3 alone induced a current in oocytes expressing alpha1beta2gamma2L, alpha6beta2gamma2L and beta2gamma2L constructs. This current displayed a reversal potential identical to that of GABA-gated chloride currents, and was blocked by picrotoxin (10 microM), but not by bicuculline (50 microM), indicating that T3 gates the chloride channel by binding to a site other than the GABA-binding site. The direct channel-gating action of T3 was concentration-dependent, with an EC50 of 23 +/- 5 microM. The actions of T3 are unique in that T3 acts as a noncompetitive antagonist in the presence of GABA but can directly gate the chloride channel in the absence of GABA.