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

We have previously shown that triiodothyronine (T3) inhibits γ- 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 μM in oocytes coexpressing α₁ β₂ γ(2L) receptor subunits. T3 had no inhibitory effect on α₆ β₂ γ(2L) or β₂ γ(2L) receptor constructs, indicating that the α₁ 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 α₁ β₂ γ(2L), α₆ β₂ γ(2L) and β₂ γ(2L) constructs. This current displayed a reversal potential identical to that of GABA-gated chloride currents, and was blocked by picrotoxin (10 μM), but not by bicuculline (50 μM), 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 μM. 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.