gamma-Aminobutyric acid, acting through gamma -aminobutyric acid type A receptors, inhibits the biosynthesis of neurosteroids in the frog hypothalamus.

Do-Rego JL; Mensah-Nyagan GA; Beaujean DVaudry DSieghart WLuu-The VPelletier GVaudry H

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gamma-Aminobutyric acid, acting through gamma -aminobutyric acid type A receptors, inhibits the biosynthesis of neurosteroids in the frog hypothalamus.

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摘要

Most of the actions of neurosteroids on the central nervous system are mediated through allosteric modulation of the gamma-aminobutyric acid type A (GABA(A)) receptor, but a direct effect of GABA on the regulation of neurosteroid biosynthesis has never been investigated. In the present report, we have attempted to determine whether 3beta-hydroxysteroid dehydrogenase (3beta-HSD)-containing neurons, which secrete neurosteroids in the frog hypothalamus, also express the GABA(A) receptor, and we have investigated the effect of GABA on neurosteroid biosynthesis by frog hypothalamic explants. Double immunohistochemical labeling revealed that most 3beta-HSD-positive neurons also contain GABA(A) receptor alpha(3) and beta(2)/beta(3) subunit-like immunoreactivities. Pulse-chase experiments showed that GABA inhibited in a dose-dependent manner the conversion of tritiated pregnenolone into radioactive steroids, including 17-hydroxy-pregnenolone, progesterone, 17-hydroxy-progesterone, dehydroepiandrosterone, and dihydrotestosterone. The effect of GABA on neurosteroid biosynthesis was mimicked by the GABA(A) receptor agonist muscimol but was not affected by the GABA(B) receptor agonist baclofen. The selective GABA(A) receptor antagonists bicuculline and SR95531 reversed the inhibitory effect of GABA on neurosteroid formation. The present results indicate that steroid-producing neurons of the frog hypothalamus express the GABA(A) receptor alpha(3) and beta(2)/beta(3) subunits. Our data also demonstrate that GABA, acting on GABA(A) receptors at the hypothalamic level, inhibits the activity of several key steroidogenic enzymes, including 3beta-HSD and cytochrome P450(C17) (17alpha-hydroxylase).

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来源
《Proceedings of the National Academy of Sciences of the United States of America》 |2000年第25期|13925-13930|共6页
作者
Do-Rego JL; Mensah-Nyagan GA; Beaujean DVaudry DSieghart WLuu-The VPelletier GVaudry H;
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作者单位

European Institute for Peptide Research (IFRMP 23), Laboratory of Cellular and Molecular Neuroendocrinology, Institut National de la Sante et de la Recherche Medicale, Unite 413, Centre National de la Recherche Scientifique, University of Rouen, Fran;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
GABA; Hypothalamus; Receptors; GABA-A; Steroids; 下丘脑; 受体; 甾类;

gamma-Aminobutyric acid, acting through gamma -aminobutyric acid type A receptors, inhibits the biosynthesis of neurosteroids in the frog hypothalamus.

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