Estrogen receptor alpha (ERα) has been recognized now for several decades as playing a key role in reproduction and exerting functions in numerous nonreproductive tissues. In this review, we attempt to summarize the in vitro studies that are the basis of our current understanding of the mechanisms of action of ERα as a nuclear receptor and the key roles played by its two activation functions (AFs) in its transcriptional activities. We then depict the consequences of the selective inactivation of these AFs in mouse models, focusing on the prominent roles played by ERα in the reproductive tract and in the vascular system. Evidence has accumulated over the two last decades that ERα is also associated with the plasma membrane and activates non-nuclear signaling from this site. These rapid/nongenomic/membrane-initiated steroid signals (MISS) have been characterized in a variety of cell lines, and in particular in endothelial cells. The development of selective pharmacological tools that specifically activate MISS and the generation of mice expressing an ERα protein impeded for membrane localization have begun to unravel the physiological role of MISS in vivo. Finally, we discuss novel perspectives for the design of tissue-selective ER modulators based on the integration of the physiological and pathophysiological roles of MISS actions of estrogens.

中文翻译：

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膜和核雌激素受体的阿尔法作用：从组织特异性到医学意义。

几十年来，雌激素受体α（ERα）已被公认为在许多非生殖组织的生殖中发挥关键作用。在这篇综述中，我们试图总结体外研究，这些研究是我们目前了解ERα作为核受体的作用机理以及其两个激活功能（AF）在其转录活性中起关键作用的基础。然后，我们在小鼠模型中描绘了这些AF选择性失活的后果，重点是ERα在生殖道和血管系统中发挥的重要作用。在过去的二十年中，已经积累了证据，证明ERα也与质膜相关，并激活了该部位的非核信号。这些快速/非基因组/膜启动的类固醇信号（MISS）已在多种细胞系中，尤其是在内皮细胞中得到了表征。选择性激活MISS的选择性药理学工具的开发以及表达受膜定位限制的ERα蛋白的小鼠的产生已经开始揭示MISS在体内的生理作用。最后，我们讨论了基于MISS雌激素作用的生理和病理生理作用整合的组织选择性ER调节剂设计的新颖观点。选择性激活MISS的选择性药理学工具的开发以及表达受膜定位限制的ERα蛋白的小鼠的产生已经开始揭示MISS在体内的生理作用。最后，我们讨论了基于MISS雌激素作用的生理和病理生理作用整合的组织选择性ER调节剂设计的新颖观点。选择性激活MISS的选择性药理学工具的开发以及表达受膜定位限制的ERα蛋白的小鼠的产生已经开始揭示MISS在体内的生理作用。最后，我们讨论了基于MISS雌激素作用的生理和病理生理作用整合的组织选择性ER调节剂设计的新颖观点。