Thyroid hormonal modulation of the binding and activity of the GABA(A) receptor complex of brain

J. V. Martin; D. B. Williams; R. M. Fitzgerald; H. K. Im; P. F. Vonvoigtlander

doi:10.1016/0306-4522(96)00052-8

Thyroid hormonal modulation of the binding and activity of the GABA(A) receptor complex of brain

J. V. Martin, D. B. Williams, R. M. Fitzgerald, H. K. Im, P. F. Vonvoigtlander

Research output: Contribution to journal › Article › peer-review

66 Scopus citations

Abstract

Thyroid hormones, which are known to act by genomic mechanisms in peripheral tissues, were found to influence the binding and function of the GABA(A) receptor complex in brain membranes. Submicromolar concentrations of triiodothyronine and thyroxine stereospecifically stimulated the binding of [³⁵S]t-butylbicyclophosphorothionate (a convulsant ligand for the GABA(A) receptor complex) to highly washed rat brain membranes, while higher concentrations of the hormones inhibited radioligand binding. GABA-stimulated ³⁶Cl^- flux in isolated brain membrane sacs was inhibited by L- triiodothyronine with a half-maximally inhibitory concentration (IC₅₀) of 10^-7 M. Patch-clamp analysis of recombinant GABA(A) receptor subunits expressed in human embryonic kidney-293 cells showed an inhibition of chloride currents by thyroid hormones. This effect required only the α₁β₂ subunits, and was not blocked by the benzodiazepine antagonist flumazenil. Since thyroid hormones are known to he concentrated in nerve terminal preparations and subsequently released, the hormones may have non-genomic mechanisms of action as putative neurotransmitters or neuromodulators in brain and act through GABA(A) receptors.

Original language	English (US)
Pages (from-to)	705-713
Number of pages	9
Journal	Neuroscience
Volume	73
Issue number	3
DOIs	https://doi.org/10.1016/0306-4522(96)00052-8
State	Published - Aug 1996

All Science Journal Classification (ASJC) codes

Neuroscience(all)

Keywords

GABA(A) receptor
chloride flux
human embryonic kidney (HEK-293) cells
neurosteroid
synaptosomes
t-butylbicyclophosphorothionate (TBPS)

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10.1016/0306-4522(96)00052-8

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title = "Thyroid hormonal modulation of the binding and activity of the GABA(A) receptor complex of brain",

abstract = "Thyroid hormones, which are known to act by genomic mechanisms in peripheral tissues, were found to influence the binding and function of the GABA(A) receptor complex in brain membranes. Submicromolar concentrations of triiodothyronine and thyroxine stereospecifically stimulated the binding of [35S]t-butylbicyclophosphorothionate (a convulsant ligand for the GABA(A) receptor complex) to highly washed rat brain membranes, while higher concentrations of the hormones inhibited radioligand binding. GABA-stimulated 36Cl- flux in isolated brain membrane sacs was inhibited by L- triiodothyronine with a half-maximally inhibitory concentration (IC50) of 10-7 M. Patch-clamp analysis of recombinant GABA(A) receptor subunits expressed in human embryonic kidney-293 cells showed an inhibition of chloride currents by thyroid hormones. This effect required only the α1β2 subunits, and was not blocked by the benzodiazepine antagonist flumazenil. Since thyroid hormones are known to he concentrated in nerve terminal preparations and subsequently released, the hormones may have non-genomic mechanisms of action as putative neurotransmitters or neuromodulators in brain and act through GABA(A) receptors.",

keywords = "GABA(A) receptor, chloride flux, human embryonic kidney (HEK-293) cells, neurosteroid, synaptosomes, t-butylbicyclophosphorothionate (TBPS)",

author = "Martin, {J. V.} and Williams, {D. B.} and Fitzgerald, {R. M.} and Im, {H. K.} and Vonvoigtlander, {P. F.}",

note = "Funding Information: Our observations of the effects of thyroid hormones on the GABA A receptor complex suggest a non-genomic mechanism for thyroid hormone action on some classes of neurons in the brain. Recent estimates of the concentrations of thyroid hormones in the synaptic cleft of the CNS 42 are within the range which should exert the currently described effects on GABA A receptor binding and activity. Since thyroid hormones are concentrated in nerve terminal fractions~O.~l.29 and subsequently released, 42 these findings support earlier suggestions of a possible role of thyroid hormones as neurotransmitters or neuro-modulators in brain. 9'42 Acknowledgements--The authors are grateful to Dr Mary Dratman for her helpful discussions of the work. This research was supported by grants from the Rutgers University Busch Fund and the National Science Foundation (IBN 94-12109) to JVM.",

year = "1996",

month = aug,

doi = "10.1016/0306-4522(96)00052-8",

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journal = "Neuroscience",

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T1 - Thyroid hormonal modulation of the binding and activity of the GABA(A) receptor complex of brain

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AU - Williams, D. B.

AU - Fitzgerald, R. M.

AU - Im, H. K.

AU - Vonvoigtlander, P. F.

N1 - Funding Information: Our observations of the effects of thyroid hormones on the GABA A receptor complex suggest a non-genomic mechanism for thyroid hormone action on some classes of neurons in the brain. Recent estimates of the concentrations of thyroid hormones in the synaptic cleft of the CNS 42 are within the range which should exert the currently described effects on GABA A receptor binding and activity. Since thyroid hormones are concentrated in nerve terminal fractions~O.~l.29 and subsequently released, 42 these findings support earlier suggestions of a possible role of thyroid hormones as neurotransmitters or neuro-modulators in brain. 9'42 Acknowledgements--The authors are grateful to Dr Mary Dratman for her helpful discussions of the work. This research was supported by grants from the Rutgers University Busch Fund and the National Science Foundation (IBN 94-12109) to JVM.

PY - 1996/8

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N2 - Thyroid hormones, which are known to act by genomic mechanisms in peripheral tissues, were found to influence the binding and function of the GABA(A) receptor complex in brain membranes. Submicromolar concentrations of triiodothyronine and thyroxine stereospecifically stimulated the binding of [35S]t-butylbicyclophosphorothionate (a convulsant ligand for the GABA(A) receptor complex) to highly washed rat brain membranes, while higher concentrations of the hormones inhibited radioligand binding. GABA-stimulated 36Cl- flux in isolated brain membrane sacs was inhibited by L- triiodothyronine with a half-maximally inhibitory concentration (IC50) of 10-7 M. Patch-clamp analysis of recombinant GABA(A) receptor subunits expressed in human embryonic kidney-293 cells showed an inhibition of chloride currents by thyroid hormones. This effect required only the α1β2 subunits, and was not blocked by the benzodiazepine antagonist flumazenil. Since thyroid hormones are known to he concentrated in nerve terminal preparations and subsequently released, the hormones may have non-genomic mechanisms of action as putative neurotransmitters or neuromodulators in brain and act through GABA(A) receptors.

AB - Thyroid hormones, which are known to act by genomic mechanisms in peripheral tissues, were found to influence the binding and function of the GABA(A) receptor complex in brain membranes. Submicromolar concentrations of triiodothyronine and thyroxine stereospecifically stimulated the binding of [35S]t-butylbicyclophosphorothionate (a convulsant ligand for the GABA(A) receptor complex) to highly washed rat brain membranes, while higher concentrations of the hormones inhibited radioligand binding. GABA-stimulated 36Cl- flux in isolated brain membrane sacs was inhibited by L- triiodothyronine with a half-maximally inhibitory concentration (IC50) of 10-7 M. Patch-clamp analysis of recombinant GABA(A) receptor subunits expressed in human embryonic kidney-293 cells showed an inhibition of chloride currents by thyroid hormones. This effect required only the α1β2 subunits, and was not blocked by the benzodiazepine antagonist flumazenil. Since thyroid hormones are known to he concentrated in nerve terminal preparations and subsequently released, the hormones may have non-genomic mechanisms of action as putative neurotransmitters or neuromodulators in brain and act through GABA(A) receptors.

KW - GABA(A) receptor

KW - chloride flux

KW - human embryonic kidney (HEK-293) cells

KW - neurosteroid

KW - synaptosomes

KW - t-butylbicyclophosphorothionate (TBPS)

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JO - Neuroscience

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ER -

Thyroid hormonal modulation of the binding and activity of the GABA(A) receptor complex of brain

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