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

Estrogens regulate physiological and pathological processes in both women and men. Traditionally, the actions of 17β-estradiol, the predominant and most potent endogenous estrogen, were ascribed to two nuclear estrogen receptors (ERs), ERα and ERβ; however, transmembrane ERs, such as G-protein-coupled ER 1 (GPER), have been implicated in rapid estrogen signaling. This Review provides an overview of estrogen signaling and its receptors, with particular emphasis on GPER. It also highlights the importance of GPER in health and disease, such as cancer, for which GPER is a potential therapeutic target and prognostic indicator. 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.