DIRECT CHANNEL-GATING AND MODULATORY EFFECTS OF TRIIODOTHYRONINE ON RECOMBINANT GABA(A) RECEPTORS

We have previously shown that triiadothyronine (T3) inhibits gamma-ami nobutyric acid type A (GABA(A)) receptors in synaptoneurosomes and tra nsfected 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 inhibite d GABA-gated chloride currents in a non-competitive manner and yielded an IC50 of 7.3 +/- 0.8 mu M in oocytes coexpressing alpha(1)beta(2)ga mma(2L) receptor subunits. T3 had no inhibitory effect on alpha(6)beta (2)gamma(2L) or beta(2)gamma(2L) receptor constructs, indicating that the alpha(1) subunit imparts T3 sensitivity to the receptor. In additi on to the inhibitory effect of T3 on GABA responses, T3 alone induced a current in oocytes expressing alpha(1 )beta(2)gamma(2L), alpha(6)bet a(2)gamma(2L) and beta(2)gamma(2L) constructs. This current displayed a reversal potential identical to that of GABA-gated chloride currents , and was blocked by picrotoxin (10 mu M), but not by bicuculline (50 mu M), indicating that T3 gates the chloride channel by binding to a s ite other than the GABA-binding site. The direct channel-gating action of T3 was concentration-dependent, with an EC50 of 23 +/- 5 mu M. The actions of T3 are unique in that T3 acts as a noncompetitive antagoni st in the presence of GABA but can directly gate the chloride channel in the absence of GABA. (C) 1998 Elsevier Science B.V. All rights rese rved.