Estrogen biology: new insights into GPER function and clinical opportunities

Abstract

Estrogens play an important role in the regulation of normal physiology, aging and many disease states. Although the nuclear estrogen receptors have classically been described to function as ligand-activated transcription factors mediating genomic effects in hormonally regulated tissues, more recent studies reveal that estrogens also mediate rapid signaling events traditionally associated with G protein-coupled receptors. The G protein-coupled estrogen receptor GPER (formerly GPR30) has now become recognized as a major mediator of estrogen's rapid cellular effects throughout the body. With the discovery of selective synthetic ligands for GPER, both agonists and antagonists, as well as the use of GPER knockout mice, significant advances have been made in our understanding of GPER function at the cellular, tissue and organismal levels. In many instances, the protective/beneficial effects of estrogen are mimicked by selective GPER agonism and are absent or reduced in GPER knockout mice, suggesting an essential or at least parallel role for GPER in the actions of estrogen. In this review, we will discuss recent advances and our current understanding of the role of GPER and the activity of clinically used drugs, such as SERMs and SERDs, in physiology and disease. We will also highlight novel opportunities for clinical development towards GPER-targeted therapeutics, for molecular imaging, as well as for theranostic approaches and personalized medicine.

Keywords: 17β-Estradiol; Cardiac; Cardiovascular; GPR30; Immune; SERM.

Figure 1

Ligands of GPER and ERs. Agonists (green arrows), partial agonists (SERMS, orange arrow) and antagonists (red arrows) of GPER and the classical estrogen receptors ER and ER. SERMS and SERDs that f. SERMS and SERDs that function as ER antagonists in many tissues act as agonists of GPER. GPER-selective ligands (G-1, G15 and G36) are highly selective for GPER over ERs. Modified from (Meyer et al., 2011b), with permission of Elsevier Publishers.

Figure 2

Signaling pathways initiated by GPER and ERs. Endogenous estrogens, including 17 -estradiol (E2), represent nonselective activators of the three known ERs, ER, ER and GPER. Estrogen activates nuclear ERs, inducing dimerization of the receptors and binding of receptor dimers to target gene promoters. Alternatively, activated ERs modulate the function of other classes of transcription factors (TFs) through protein-protein interactions. Subpopulations of ERs at the plasma membrane following activation by estrogen interact with adaptor proteins (adaptor) and signaling molecules such as c-src, which mediates rapid signaling via PI3K/Akt and MAPK pathways. GPER, which is predominantly localized intracellularly, can be activated by estrogen, or selective GPER agonists (such as G-1), but also by selective estrogen receptor downregulators (such as fulvestrant), or selective estrogen receptor modulators (such as tamoxifen and raloxifene). GPER activation stimulates cAMP production, calcium mobilization and c-src, which activates MMPs. These MMPs cleave pro-HB-EGF, releasing free HB-EGF that transactivates EGFR, which in turn activates MAPK and PI3K/Akt pathways that can induce additional rapid (nongenomic) effects (X), or genomic effects regulating gene transcription. Estrogen-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. Abbreviations: E2, 17 - estradiol; EGFR, epidermal growth factor receptor; ER, estrogen receptor; GPER, G-protein-coupled ER; MMP, matrix metalloproteinase; pro-HB-EGF, pro-heparin-binding epidermal growth factor; TF, transcription factor. Figure reproduced from (Prossnitz and Barton, 2011).

Figure 3

Current experimental and clinical evidence implicates a physiological role (shown in black) for GPER in neuroendocrine and cerebral functions, immunity and immune cell function, metabolic and endocrine regulation, vascular, myocardial, and kidney function, as well as development and reproductive functions. In addition, data obtained in experimental models of disease and/or tissue from patients with disease suggest roles for GPER in pathological conditions (shown in red), such as diabetes mellitus, arterial hypertension, proteinuric renal disease, osteoporosis, arthritis, immune diseases, such as multiple sclerosis, and cancer. Targeting GPER activity with highly selective ligands in humans may represent a novel approach for the treatment of these conditions, for molecular imaging, as well as for theranostic approaches and personalized medicine. Figure reproduced from (Prossnitz and Barton, 2011).