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Physiol Rev. 2017 Jul 1;97(3):1045-1087. doi: 10.1152/physrev.00024.2016.

Membrane and Nuclear Estrogen Receptor Alpha Actions: From Tissue Specificity to Medical Implications.

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I2MC, Institut National de la Santé et de la Recherche Médicale (INSERM) U 1048, Université de Toulouse 3 and CHU de Toulouse, Toulouse, France; Equipe SP@RTE UMR 6290 CNRS, Institut de Genétique et Développement de Rennes, Université de Rennes 1, Campus de Beaulieu, Rennes, France; Université de Rennes 1, Institut de Recherche en Santé, Environnement et Travail (Irest-INSERM UMR 1085), Equipe TREC, Rennes, France; Unité Mixte de Recherche 6214, Centre National de la Recherche Scientifique, Angers, France; Institut de Génétique et de Biologie Moléculaire et Cellulaire, Collège de France, Université de Strasbourg, Illkirch, France; Departments of Physiology and Cell Biology and of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois.


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.

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