GABA-dependent modulation of the Cl- ionophore by steroids in rat brain

Kelvin W. Gee; Wen Chung Chang; Roberta E. Brinton; Bruce S. McEwen

doi:10.1016/0014-2999(87)90317-7

GABA-dependent modulation of the Cl^- ionophore by steroids in rat brain

Kelvin W. Gee, Wen Chung Chang, Roberta E. Brinton, Bruce S. McEwen

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

187 Scopus citations

Abstract

Steroids inhibit the binding of [³⁵S]t-butylbicyclophosphorothionate ([³⁵S]TBPS) to the GABA_A-benzodiazepine receptor (GBR) linked Cl^- ionophore in a GABA dependent manner but not through the GABA_A receptor. The most potent steroid evaluated is a naturally occuring metabolite of progesterone, 3 α-hydroxy,5 α-dihydroprogesterone with an IC₅₀ of ≈ 17 nM. Structural requirements necessary for inhibitory activity coincide with those reported for anticonvulsant and anesthetic actions. Coupled with earlier evidence that these steroids do not act directly at the benzodiazepine receptor nor the [³⁵S]TBPS labeled site to modulate the Cl^- ionophore, the possibility is proposed that a distinct membrane-bound 'steroid site' coupled to the GBR-Cl^- ionophore complex exists.

Original language	English (US)
Pages (from-to)	419-423
Number of pages	5
Journal	European Journal of Pharmacology
Volume	136
Issue number	3
DOIs	https://doi.org/10.1016/0014-2999(87)90317-7
State	Published - Apr 29 1987
Externally published	Yes

Keywords

Anesthetics
Anticonvulsants
Chloride channels
GABA
Progesterone
Steroids

ASJC Scopus subject areas

Pharmacology

Access to Document

10.1016/0014-2999(87)90317-7

Cite this

@article{24f89c46c32d49df97d4bcd9d42a0668,

title = "GABA-dependent modulation of the Cl- ionophore by steroids in rat brain",

abstract = "Steroids inhibit the binding of [35S]t-butylbicyclophosphorothionate ([35S]TBPS) to the GABAA-benzodiazepine receptor (GBR) linked Cl- ionophore in a GABA dependent manner but not through the GABAA receptor. The most potent steroid evaluated is a naturally occuring metabolite of progesterone, 3 α-hydroxy,5 α-dihydroprogesterone with an IC50 of ≈ 17 nM. Structural requirements necessary for inhibitory activity coincide with those reported for anticonvulsant and anesthetic actions. Coupled with earlier evidence that these steroids do not act directly at the benzodiazepine receptor nor the [35S]TBPS labeled site to modulate the Cl- ionophore, the possibility is proposed that a distinct membrane-bound 'steroid site' coupled to the GBR-Cl- ionophore complex exists.",

keywords = "Anesthetics, Anticonvulsants, Chloride channels, GABA, Progesterone, Steroids",

author = "Gee, {Kelvin W.} and Chang, {Wen Chung} and Brinton, {Roberta E.} and McEwen, {Bruce S.}",

note = "Funding Information: The authors wish to thank Dr. Kay Jorgensen for the gifts of 3a,5a-DHP, 3a,5a-THDC and alphaxalone. This work was supported in part by a Research Starter Grant (K.W.G.) from the Pharmaceutical Manufacturer's Association Foundation (P.M.A.F.), and NIH Grants MH-41256 (B.S.M.) and MH-09224 (R.E.B.). K.W.G. is a recipient of a Faculty Development Award in Basic Pharmacology from the PMAF.",

year = "1987",

month = apr,

day = "29",

doi = "10.1016/0014-2999(87)90317-7",

language = "English (US)",

volume = "136",

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T1 - GABA-dependent modulation of the Cl- ionophore by steroids in rat brain

AU - Gee, Kelvin W.

AU - Chang, Wen Chung

AU - Brinton, Roberta E.

AU - McEwen, Bruce S.

N1 - Funding Information: The authors wish to thank Dr. Kay Jorgensen for the gifts of 3a,5a-DHP, 3a,5a-THDC and alphaxalone. This work was supported in part by a Research Starter Grant (K.W.G.) from the Pharmaceutical Manufacturer's Association Foundation (P.M.A.F.), and NIH Grants MH-41256 (B.S.M.) and MH-09224 (R.E.B.). K.W.G. is a recipient of a Faculty Development Award in Basic Pharmacology from the PMAF.

PY - 1987/4/29

Y1 - 1987/4/29

N2 - Steroids inhibit the binding of [35S]t-butylbicyclophosphorothionate ([35S]TBPS) to the GABAA-benzodiazepine receptor (GBR) linked Cl- ionophore in a GABA dependent manner but not through the GABAA receptor. The most potent steroid evaluated is a naturally occuring metabolite of progesterone, 3 α-hydroxy,5 α-dihydroprogesterone with an IC50 of ≈ 17 nM. Structural requirements necessary for inhibitory activity coincide with those reported for anticonvulsant and anesthetic actions. Coupled with earlier evidence that these steroids do not act directly at the benzodiazepine receptor nor the [35S]TBPS labeled site to modulate the Cl- ionophore, the possibility is proposed that a distinct membrane-bound 'steroid site' coupled to the GBR-Cl- ionophore complex exists.

AB - Steroids inhibit the binding of [35S]t-butylbicyclophosphorothionate ([35S]TBPS) to the GABAA-benzodiazepine receptor (GBR) linked Cl- ionophore in a GABA dependent manner but not through the GABAA receptor. The most potent steroid evaluated is a naturally occuring metabolite of progesterone, 3 α-hydroxy,5 α-dihydroprogesterone with an IC50 of ≈ 17 nM. Structural requirements necessary for inhibitory activity coincide with those reported for anticonvulsant and anesthetic actions. Coupled with earlier evidence that these steroids do not act directly at the benzodiazepine receptor nor the [35S]TBPS labeled site to modulate the Cl- ionophore, the possibility is proposed that a distinct membrane-bound 'steroid site' coupled to the GBR-Cl- ionophore complex exists.

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