concept

Estrogen receptor alpha (ERα)

he physiological functions of estrogenic compounds are modulated largely by the estrogen receptors subtypes alpha (ERα) and beta (ERβ). These proteins have actions in the cell nucleus, regulating transcription of specific target genes by binding to associated DNA regulatory sequences. In humans, both receptor subtypes are expressed in many cells and tissues, and they control key physiological functions in various organ systems, such as reproductive, skeletal, cardiovascular and central nervous systems, as well as in specific tissues (such as breast and sub-compartments of prostate and ovary). ERα is present mainly in mammary gland, uterus, ovary (thecal cells), bone, male reproductive organs (testes and epididymis), prostate (stroma), liver, and adipose tissue. By contrast, ERβ is found mainly in the prostate (epithelium), bladder, ovary (granulosa cells), colon, adipose tissue, and immune system. Both subtypes are markedly expressed in the cardiovascular and central nervous systems. There are some common physiological roles for the two ERs, such as in the development and function of the ovaries, and in the protection of the cardiovascular system. The alpha subtype has a more prominent role on the mammary gland and uterus, as well as on the preservation of skeletal homeostasis and the regulation of metabolism. The beta subtype seems to have a more profound effect on the central nervous and immune systems, and it generally counteracts the ERα-promoted cell hyperproliferation in tissues such as breast and uterus [2–3]. In many breast cancers, ERα activation by estrogens is generally considered responsible for enhanced proliferation, whereas this is counteracted by the presence of ERβ, which exerts an antiproliferative effect [9]. Activation of both ERα and ERβ caused a neuroprotective effect, in particular against toxicity associated with Aβ accumulation, therefore suggesting a potential role in the prevention and treatment of Alzheimer’s disease [26]. In animal models, ERα proved to play a key role in the prevention and treatment of multiple sclerosis, which was superior to that of ERβ [27]. ERα is highly expressed in endothelial cells and plays a role in mediating the effects of estrogens in the vascular endothelium, whereas ERβ stimulates the production of nitric oxide. Therefore, the activation of both receptors has a beneficial hypotensive effect caused by vascular wall dilation [31–32]. A recent study [33] demonstrated that the non-nuclear fraction of ERα, which is linked to plasma membrane, is selectively responsible for the vascular actions elicited by estrogens, such as rapid dilatation, acceleration of endothelial repair, and endothelial NO production. This observation is particularly useful since a selective cytoplasmic stimulation of ERα would promote a beneficial cardioprotective effect, without eliciting all those side effects associated to nuclear activation of this receptor. Estrogen replacement therapy (ERT) is clinically used to prevent osteoporosis [35]; however, long-term ERT may stimulate proliferation of breast and uterus through ERα, increasing the risk of cancer in these organs. Bone cells express both estrogen receptor, ERα and ERβ, although ERα seems to play the major role [36]. ERβ may play an important role in regulating metabolic pathway and adipose tissue function [38].

Ref:
Paterni I, Granchi C, Katzenellenbogen JA, Minutolo F. Estrogen receptors alpha (ERα) and beta (ERβ): subtype-selective ligands and clinical potential. Steroids. 2014 Nov;90:13-29. doi: 10.1016/j.steroids.2014.06.012. Epub 2014 Jun 24. PMID: 24971815; PMCID: PMC4192010.

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Added on Oct 23, 2022 by Barbara Van De Keer

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