Membrane and nuclear estrogen receptor alpha actions: From tissue specificity to medical implications

Jean Francois Arnal, Françoise Lenfant, Raphaël Metivier, Gilles Flouriot, Daniel Henrion, Marine Adlanmerini, Coralie Fontaine, Pierre Gourdy, Pierre Chambon, Benita Katzenellenbogen, John Katzenellenbogen

Research output: Contribution to journalReview articlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)1045-1087
Number of pages43
JournalPhysiological Reviews
Issue number3
StatePublished - Jul 2017

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Physiology (medical)


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