Twenty years of the G protein-coupled estrogen receptor GPER: Historical and personal perspectives

Abstract

Estrogens play a critical role in many aspects of physiology, particularly female reproductive function, but also in pathophysiology, and are associated with protection from numerous diseases in premenopausal women. Steroids and the effects of estrogen have been known for ∼90 years, with the first evidence for a receptor for estrogen presented ∼50 years ago. The original ancestral steroid receptor, extending back into evolution more than 500 million years, was likely an estrogen receptor, whereas G protein-coupled receptors (GPCRs) trace their origins back into history more than one billion years. The classical estrogen receptors (ERα and ERβ) are ligand-activated transcription factors that confer estrogen sensitivity upon many genes. It was soon apparent that these, or novel receptors may also be responsible for the "rapid"/"non-genomic" membrane-associated effects of estrogen. The identification of an orphan GPCR (GPR30, published in 1996) opened a new field of research with the description in 2000 that GPR30 expression is required for rapid estrogen signaling. In 2005-2006, the field was greatly stimulated by two studies that described the binding of estrogen to GPR30-expressing cell membranes, followed by the identification of a GPR30-selective agonist (that lacked binding and activity towards ERα and ERβ). Renamed GPER (G protein-coupled estrogen receptor) by IUPHAR in 2007, the total number of articles in PubMed related to this receptor recently surpassed 1000. In this article, the authors present personal perspectives on how they became involved in the discovery and/or advancement of GPER research. These areas include non-genomic effects on vascular tone, receptor cloning, molecular and cellular biology, signal transduction mechanisms and pharmacology of GPER, highlighting the roles of GPER and GPER-selective compounds in diseases such as obesity, diabetes, and cancer and the obligatory role of GPER in propagating cardiovascular aging, arterial hypertension and heart failure through the stimulation of Nox expression.

Estrogen receptor signaling mechanisms

“…In terms of structure, GPER1 does not share similarities with ERα or ERβ. As a typical G protein coupled receptor, its structure consists of 7 transmembrane α-helical regions, 4 extracellular segments, and 4 cytosolic segments (Barton et al, 2018). This receptor has low binding affinity (17B-estradiol) when compared to other estrogen receptors (Prossnitz & Barton, 2014).…”

“…Both the membrane bound estrogen receptor GPER1, and some variants of the ERα and ERβ have been associated to non-genomic estrogen signaling (Barton et al, 2018; E. J. Filardo & Thomas, 2012).…”

Membrane estrogen receptor (GPER) and follicle-stimulating hormone receptor heteromeric complexes promote human ovarian follicle survival

“…A greater proportion of FSHR only complexes would thus program the cell fate toward FSHR/cAMP-dependent death, a finding well described in the literature [5][6][7]9,[55][56][57][58][59] but neglected for a long-time due to the lack of evidence on the pro-apoptotic action of FSH in vivo. Indeed, FSH action is commonly associated with 32 proliferative events, follicular growth being the physiological example, and as suggested by the presence of FSHR in pathological contexts characterized by uncontrolled cell growth, such as cancer 28 or endometriosis 29 , which indicated FSHR as a target of anti-cancer drugs 30 .…”

“…Consistent with its impact on cell growth, FSHR expression was found in pathological contexts characterized by uncontrolled cell proliferation, such as tumors 28 or endometriosis 29 , suggesting that it could be a target for still outstanding anti-cancer therapies 30 . Similarly, GPER expression has been described in several tumor cells 31 , including breast, endometrium and ovary 32 , where it may cooperate with FSHR in inducing uncontrolled cell proliferation 27,33 .…”

G Protein–Coupled Estrogen Receptor Production Using an Escherichia coli Cell‐Free Expression System

“…GPER was formerly known as the orphan receptor GPR30 until growing evidence suggested that its activity was modulated by endogenous estrogens and estrogenic compounds (Barton et al., ). Evidence included correlating nongenomic estrogen‐mediated signaling events with calcium and cAMP flux, EGFR activity, and the MAPK‐ERK1/2 cascade (Filardo, Quinn, & Frackelton, ; Revankar, Cimino, Sklar, Arterburn, & Prossnitz, ).…”