Mani Shaila K, Reyna Andrea M, Chen Jian Zhong, Mulac-Jericevic Biserka, Conneely Orla M
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Mol Endocrinol. 2006 Jun;20(6):1322-32. doi: 10.1210/me.2005-0466. Epub 2006 Feb 16.
Neurobehavioral effects of progesterone are mediated primarily by its interaction with neural progesterone receptors (PRs), expressed as PR-A and PR-B protein isoforms. Whereas the expression of two isoforms in the neural tissues is suggestive of their selective cellular responses and modulation of distinct subsets of PR-induced target genes, the role of individual isoforms in brain and behavior is unknown. We have previously demonstrated a critical role for PRs as transcriptional mediators of progesterone (ligand-dependent), and dopamine (ligand-independent)-facilitated female reproductive behavior in female mice lacking both the isoforms of PR. To further elucidate the selective contribution of the individual PR isoforms in female sexual receptive behavior, we used the recently generated PR-A and PR-B isoform-specific null mutant mice. We present evidence for differential responses of each isoform to progesterone and dopamine agonist, SKF 81297 (SKF), and demonstrate a key role for PR-A isoform in both hormone-dependent and -independent facilitation of sexual receptive behavior. Interestingly, whereas both the isoforms were essential for SKF-facilitated sexual behavior, PR-A appeared to play a more important role in the 8-bromo-cAMP-facilitated lordosis response, raising the possibility of distinct intracellular signaling pathways mediating the responses. Finally, we also demonstrate that antiprogestin, RU38486, was an effective inhibitor of PR-A-mediated, progesterone-dependent, but not SKF or 8-bromo-cAMP-dependent sexual receptivity. The data reveal the selective contributions of individual isoforms to the signaling pathways mediating female reproductive behavior.
孕酮的神经行为效应主要是通过其与神经孕酮受体（PRs）的相互作用介导的，PRs以PR - A和PR - B蛋白异构体的形式表达。虽然神经组织中这两种异构体的表达表明它们具有选择性细胞反应以及对PR诱导的不同靶基因子集的调节作用，但单个异构体在大脑和行为中的作用尚不清楚。我们之前已经证明，在缺乏PR两种异构体的雌性小鼠中，PRs作为孕酮（配体依赖性）和多巴胺（配体非依赖性）促进雌性生殖行为的转录介质发挥关键作用。为了进一步阐明单个PR异构体在雌性性接受行为中的选择性作用，我们使用了最近培育出的PR - A和PR - B异构体特异性基因敲除突变小鼠。我们提供了证据，表明每种异构体对孕酮和多巴胺激动剂SKF 81297（SKF）有不同反应，并证明PR - A异构体在激素依赖性和非依赖性促进性接受行为中起关键作用。有趣的是，虽然两种异构体对于SKF促进的性行为都是必不可少的，但PR - A在8 - 溴 - cAMP促进的脊柱前凸反应中似乎发挥了更重要的作用，这增加了介导这些反应的不同细胞内信号通路的可能性。最后，我们还证明，抗孕激素RU38486是PR - A介导的、孕酮依赖性而非SKF或8 - 溴 - cAMP依赖性性接受的有效抑制剂。这些数据揭示了单个异构体对介导雌性生殖行为的信号通路的选择性作用。
