Inhibition of the activity of the native γ-aminobutyric acid A receptor by metabolites of thyroid hormones: Correlations with molecular modeling studies

Joseph V. Martin, J. Michael Padron, M. Andrew Newman, Richard Chapell, Nancy J. Leidenheimer, Luke A. Burke

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19 Scopus citations

Abstract

To characterize the direct effects of thyroid hormones on native γ-aminobutyric acidA (GABAA) receptors, rapid (5 s) actions of a series of iodothyronines on muscimol-stimulated uptake of 36Cl- were investigated in synaptoneurosomes prepared from rat brain. The results were correlated with molecular modeling of the active compounds. Dose-response curves for muscimol in the presence of 3,3′, 5-L-triiodothyronine (L-T3) indicated a noncompetitive inhibition of muscimol-stimulated 36Cl- uptake by the thyroid hormone. Synaptoneurosomes prepared from cerebellum were less sensitive to L-T3 than those from cerebral cortex, in terms of the potency of the hormone. The overall efficacy approached complete inhibition for both brain regions. Muscimol-stimulated 36Cl- uptake was inhibited differentially by iodothyronine derivatives. One group of compounds with IC 50 values of 18-30 μM included L-thyroxine (L-T4), D-thyroxine (D-T4), 3,3′, 5,5′-tetraiodothyroacetic acid (Tetrac), and 3,3′, 5-triiodothyroacetic acid (Triac). A second group with values of 75-100 μM included 3,3′, 5′-L-triiodothyronine (reverse T3; r-T3), 3,3′-diiodo-L-thyronine (3,3′-L-T2) and 3,5-diiodo-L- thyronine (3,5-D-T2). A final group of inactive compounds with IC50 values greater than 100 μM included 3′,5′-diiodo-L-thyronine (3′,5′-L-T2), 3-iodo-L-thyronine (L-T1), 3′-iodo-L-thyronine (3′-L-T1), and L-thyronine (L-T0). Molecular modeling of the active iodothyronines using the Gaussian03 series of programs indicated close correspondences with models of the GABA-inhibitory neurosteroid pregnenolone sulfate (PREGS), suggesting common mechanisms of action at the GABAA receptor.

Original languageEnglish (US)
Pages (from-to)98-107
Number of pages10
JournalBrain research
Volume1004
Issue number1-2
DOIs
StatePublished - Apr 9 2004

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

Keywords

  • GABA receptor
  • GABA receptors
  • Iodothyronine
  • Neurosteroid
  • Neurotransmitters, modulators, transporters, and receptors
  • Pregnenolone sulfate
  • Synaptoneurosome
  • Thyroxine

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