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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >A progesterone metabolite stimulates the release of gonadotropin-releasing hormone from GT1-1 hypothalamic neurons via the gamma-aminobutyric acid type A receptor.
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A progesterone metabolite stimulates the release of gonadotropin-releasing hormone from GT1-1 hypothalamic neurons via the gamma-aminobutyric acid type A receptor.

机译：孕酮代谢产物通过γ-氨基丁酸A型受体刺激从GT1-1下丘脑神经元释放促性腺激素释放激素。

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摘要

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.
机译：还原的孕酮代谢物四氢孕酮（3α-羟基-5α-pregnan-20-one； 3α，5α-THP）是A型γ-氨基丁酸（GABAA）受体的正调节剂。先前对下丘脑片段进行的体外实验表明，GABA可以调节促性腺激素释放激素（GnRH）的释放。使用GT1-1永生的GnRH神经元，我们调查了GABAA受体配体（包括3 alpha，5 alpha-THP）对GnRH释放的作用。我们首先表征了这些神经元表达的GABAA受体。 [3H]麝香酚，但不与[3H]氟硝西m结合，与GT1-1细胞膜具有高亲和力（Kd = 10.9 +/- 0.3 nM； Bmax = 979 +/- 12 fmol / mg蛋白质），和[3H] muscimol结合通过3 alpha，5 alpha-THP增强。通过逆转录酶聚合酶链反应检测到编码GABAA受体的alpha 1和beta 3亚基的mRNA。与结合数据一致，不存在结合苯二氮杂pine的γ亚基mRNA。 GnRH释放研究显示了麝香酚的剂量相关刺激作用。 3 alpha，5 alpha-THP不仅可以调节麝香酚诱导的分泌，还可以在单​​独给药时刺激GnRH释放。 Bicuculline和picrotoxin阻断了3 alpha，5 alpha-THP和麝香酚的作用。最后，我们观察到GT1-1神经元将孕酮转化为3 alpha，5 alpha-THP。我们建议孕激素可能通过膜机制增加GnRH的释放，通过其减少的代谢物3α，5α-THP作用于GABAA受体。

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