385993

A progesterone metabolite stimulates the release of gonadotropin-releasing hormone from GT1-1 hypothalamic neurons via the gamma-aminobutyric acid type A receptor.

Article date: 1995/4/25

PubMed ID: 385993

Journal name: Proceedings of the National Academy of Sciences of the United States of America (ISSN: 0027-8424)

ABSTRACT

The reduced progesterone metabolite tetrahydroprogesterone (3 alpha-hydroxy-5 alpha-pregnan-20-one; 3 alpha,5 alpha-THP) is a positive modulator of the gamma-aminobutyric acid type A (GABAA) receptor. Experiments performed in vitro with hypothalamic fragments have previously shown that GABA could modulate the release of gonadotropin-releasing hormone (GnRH). Using GT1-1 immortalized GnRH neurons, we investigated the role of GABAA receptor ligands, including 3 alpha,5 alpha-THP, on the release of GnRH. We first characterized the GABAA receptors expressed by these neurons. [3H]Muscimol, but not [3H]flunitrazepam, bound with high affinity to GT1-1 cell membranes (Kd = 10.9 +/- 0.3 nM; Bmax = 979 +/- 12 fmol/mg of protein), and [3H]muscimol binding was enhanced by 3 alpha,5 alpha-THP. mRNAs encoding the alpha 1 and beta 3 subunits of the GABAA receptor were detected by the reverse transcriptase polymerase chain reaction. In agreement with binding data, the benzodiazepine-binding gamma subunit mRNA was absent. GnRH release studies showed a dose-related stimulating action of muscimol. 3 alpha,5 alpha-THP not only modulated muscimol-induced secretion but also stimulated GnRH release when administered alone. Bicuculline and picrotoxin blocked the effects of 3 alpha,5 alpha-THP and muscimol. Finally, we observed that GT1-1 neurons convert progesterone to 3 alpha,5 alpha-THP. We propose that progesterone may increase the release of GnRH by a membrane mechanism, via its reduced metabolite 3 alpha,5 alpha-THP acting at the GABAA receptor.

Author List: el-Etr M, Akwa Y, Fiddes R J, Robel P, Baulieu E E

Publication Types: Journal Article

Substances mentioned in the article: Anti-Anxiety Agents; RNA, Messenger; Receptors, GABA-A; Muscimol; Gonadotropin-Releasing Hormone; Progesterone; Flunitrazepam; Pregnanolone;

Mesh terms: Animals; Anti-Anxiety Agents/pharmacology; Brain/physiology; Cell Line; Dose-Response Relationship, Drug; Flunitrazepam/metabolism; Gene Expression; Gonadotropin-Releasing Hormone/secretion; Hypothalamus/drug effects; Kinetics; Muscimol/metabolism; Neurons/drug effects; Pregnanolone/pharmacology; Progesterone/metabolism; RNA, Messenger/biosynthesis; Rats; Receptors, GABA-A/biosynthesis;

Citations: - 4572738

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