THYROID HORMONAL MODULATION OF THE BINDING AND ACTIVITY OF THE GABA(A) RECEPTOR COMPLEX OF BRAIN

Thyroid hormones, which are known to act by genomic mechanisms in peri pheral tissues, were found to influence the binding and function of th e GABA(A) receptor complex in brain membranes. Submicromolar concentra tions of triiodothyronine and thyroxine stereospecifically stimulated the binding of [S-35]t-butylbicyclophosphorothionate (a convulsant lig and for the GABA(A) receptor complex) to highly washed rat brain membr anes, while higher concentrations of the hormones inhibited radioligan d binding. GABA-stimulated Cl-36(-) flux in isolated brain membrane sa cs was inhibited by L-triiodothyronine with a half-maximally inhibitor y concentration (IC50) of 10(-7) M. Patch-clamp analysis of recombinan t GABA(A) receptor subunits expressed in human embryonic kidney-293 ce lls showed an inhibition of chloride currents by thyroid hormones. Thi s effect required only the alpha(1) beta(2) subunits, and was not bloc ked by the benzodiazepine antagonist flumazenil. Since thyroid hormone s are known to be concentrated in nerve terminal preparations and subs equently released, the hormones may have non-genomic mechanisms of act ion as putative neurotransmitters or neuromodulators in brain and act through GABA(A) receptors.