The classical estrogen receptors first characterized in 1958 are water-soluble proteins located in the interior of cells that are activated by estrogenenic hormones such as estradiol and several of its metabolites such as estrone or estriol. These proteins belong to the nuclear hormone receptor class of transcription factors that regulate gene transcription. Since it takes time for genes to be transcribed into RNA and translated into protein, the effects of estrogens binding to these classical estrogen receptors is delayed. However, estrogens are also known to have effects that are too fast to be caused by regulation of gene transcription. In 2005, it was discovered that a member of the G protein-coupled receptor family, GPR30 also binds with high affinity to estradiol and is responsible in part for the rapid non-genomic actions of estradiol. Based on its ability to bind estradiol, GPR30 was renamed as G protein-coupled estrogen receptor. GPER is localized in the plasma membrane but is predominantly detected in the endoplasmic reticulum.
Ligands
GPER binds estradiol with high affinity though not other endogenous estrogens, such as estrone or estriol, nor other endogenous steroids, including progesterone, testosterone, and cortisol. Although potentially involved in signaling by aldosterone, GPER does not show any detectable binding towards aldosterone. Niacin and nicotinamide bind to the receptor in vitro with very low affinity. CCL18 has been identified as an endogenous antagonist of the GPER. GPER-selective ligands include the agonist G-1 and the antagonists G15 and G36.
This protein is a member of the rhodopsin-like family of G protein-coupled receptors and is a multi-pass membrane protein that localizes to the plasma membrane. The protein binds estradiol, resulting in intracellular calcium mobilization and synthesis of phosphatidylinositol -trisphosphate in the nucleus. This protein therefore plays a role in the rapid nongenomic signaling events widely observed following stimulation of cells and tissues with estradiol. The distribution of GPER is well established in the rodent, with high expression observed in the hypothalamus, pituitary gland, adrenal medulla, kidney medulla and developing follicles of the ovary.
GPER is expressed in the blood vessel endothelium and is responsible for vasodilation and as a result, blood pressure lowering effects of 17β-estradiol. GPER also regulates components of the renin–angiotensin system, which also controls blood pressure, and is required for superoxide-mediated cardiovascular function and aging.
GPER and ERα, but not ERβ, have been found to mediate the antidepressant-like effects of estradiol. Contrarily, activation of GPER has been found to be anxiogenic in mice, while activation of ERβ has been found to be anxiolytic. There is a high expression of GPER, as well as ERβ, in oxytocin neurons in various parts of the hypothalamus, including the paraventricular nucleus and the supraoptic nucleus. It is speculated that activation of GPER may be the mechanism by which estradiol mediates rapid effects on the oxytocin system, for instance, rapidly increasing oxytocin receptor expression. Estradiol has also been found to increase oxytocin levels and release in the medial preoptic area and medial basal hypothalamus, actions that may be mediated by activation of GPER and/or ERβ. Estradiol, as well as tamoxifen and fulvestrant, have been found to rapidly induce lordosis through activation of GPER in the arcuate nucleus of the hypothalamus of female rats.
Although GPER signaling was originally thought to be tumor-promoting in breast cancer, subsequent reports suggest that nonclassical estrogen signaling is tumor suppressive in breast cancer. Consistent with this, recent studies showed that the presence of GPER protein in human breast cancer biopsies correlates with longer survival, suggesting a tumor suppressive role. In line with findings in breast cancer, GPER signaling has also been shown to be tumor suppressive in adrenocortical carcinoma, colorectal cancer, endometrial cancer, Leydig cell tumors, non-small cell lung cancer, gastric cancer, liver cancer, melanoma, osteosarcoma, ovarian cancer, and prostate cancer. Together, these reports suggest that GPER is a tumor suppressor in a wide range of cancer types, and activation of GPER may represent a new therapeutic strategy to treat cancer.
