The G-protein-coupled estrogen receptor GPER in health and disease

Abstract

Estrogens mediate profound effects throughout the body and regulate physiological and pathological processes in both women and men. The low prevalence of many diseases in premenopausal women is attributed to the presence of 17β-estradiol, the predominant and most potent endogenous estrogen. In addition to endogenous estrogens, several man-made and plant-derived molecules, such as bisphenol A and genistein, also exhibit estrogenic activity. Traditionally, the actions of 17β-estradiol are ascribed to two nuclear estrogen receptors (ERs), ERα and ERβ, which function as ligand-activated transcription factors. However, 17β-estradiol also mediates rapid signaling events via pathways that involve transmembrane ERs, such as G-protein-coupled ER 1 (GPER; formerly known as GPR30). In the past 10 years, GPER has been implicated in both rapid signaling and transcriptional regulation. With the discovery of GPER-selective ligands that can selectively modulate GPER function in vitro and in preclinical studies and with the use of Gper knockout mice, many more potential roles for GPER are being elucidated. This Review highlights the physiological roles of GPER in the reproductive, nervous, endocrine, immune and cardiovascular systems, as well as its pathological roles in a diverse array of disorders including cancer, for which GPER is emerging as a novel therapeutic target and prognostic indicator.

Figure 1

Structures of selective and nonselective estrogen receptor ligands. Compounds shown include the three major physiological forms of estrogen (17β-estradiol, estrone and estriol); the anticancer agent tamoxifen and its active metabolite 4-hydroxytamoxifen (which is both a selective estrogen receptor modulator and an agonist for GPER); fulvestrant, a selective estrogen receptor downregulator and agonist for GPER; diethylstilbestrol, a nonselective GPER agonist; the phytoestrogens genistein and coumestrol; and the xenoestrogen bisphenol A. Also shown are G-1 (a selective GPER agonist) and G15 (a selective GPER antagonist). Abbreviation: GPER, G-protein-coupled estrogen receptor 1.

Figure 2

Nongenomic and genomic estrogen signaling pathways. Endogenous estrogens including 17β-estradiol (E2) are nonselective activators of the three known estrogen receptors (ERs), ERα, ERβ and GPER. E2 activates nuclear ERs, inducing receptor dimerization, and binding of receptor dimers to the promoters of target genes. Alternatively, activated ERs modulate the function of other classes of transcription factors (TF) through protein–protein interactions. Subpopulations of ERs at the plasma membrane (mER) activated by E2 interact with adaptor proteins (adaptor) and signaling molecules such as c-Src, which mediates rapid signaling via PI3K/Akt and MAPK pathways. E2, or selective agonists such as G-1, or SERDs such as fulvestrant, or SERMs such as tamoxifen, also activate GPER, which is predominantly localized intracellularly. GPER activation stimulates cAMP production, calcium mobilization and c-Src, which activates matrix metalloproteinases (MMP). MMPs cleave pro-heparin-binding-epidermal growth factor (HB-EGF), releasing free HB-EGF that transactivates EGF receptors (EGFR). EGFR in turn activates MAPK and PI3K/Akt pathway, which can induce rapid (nongenomic) effects (X), or genomic effects regulating gene transcription. E2-mediated transcriptional regulation may involve phosphorylation (P) of ER or other TFs that may directly interact with ER, or bind independently of ER within the promoters of target genes.

Figure 3

Involvement of GPER action in regulation of physiological responses, including neuroendocrine and cerebral functions, immune cell function, endocrine regulation and metabolism, cardiovascular and kidney function, and reproductive functions. In addition, studies using experimental models of disease and/or human tissue suggest roles for GPER in diseases (such as diabetes, arterial hypertension, proteinuric renal disease, and immune diseases such as multiple sclerosis and cancer;) shown in red. Collectively, such studies suggest the therapeutic potential of regulating GPER activity as a novel approach for the treatment of these conditions.