G protein-coupled estrogen receptor 1 (GPER), also known as G protein-coupled receptor 30 (GPR30), is a protein that in humans is encoded by the GPER gene. [5] GPER binds to and is activated by the female sex hormone estradiol and is responsible for some of the rapid effects that estradiol has on cells. [6]
The classical estrogen receptors first characterized in 1958 [7] 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. [8] In 2005, it was discovered that a member of the G protein-coupled receptor (GPCR) 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). GPER is localized in the plasma membrane but is predominantly detected in the endoplasmic reticulum. [9] [8]
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. [6] [9] [10] [11] [12] Although potentially involved in signaling by aldosterone, GPER does not show any detectable binding towards aldosterone. [6] [13] [14] Niacin and nicotinamide bind to the receptor in vitro with very low affinity. [15] [16] CCL18 has been identified as an endogenous antagonist of the GPER. [17] GPER-selective ligands (that do not bind the classical estrogen receptors) include the agonist G-1 [18] and the antagonists G15 [19] and G36. [20] [6]
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 (3,4,5)-trisphosphate in the nucleus. [9] This protein therefore plays a role in the rapid nongenomic signaling events widely observed following stimulation of cells and tissues with estradiol. [21] 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. [22]
GPER expression has been studied in cancer using immunohistochemical and transcriptomic approaches, and has been detected in: colon, lung, melanoma, pancreatic [23] , breast [24] , ovarian, [25] and testicular cancer [26] .
Many groups have demonstrated that GPER signaling is tumor suppressive in cancers that are not traditionally hormone responsive, including melanoma, pancreatic, lung and colon cancer [27] [28] [29] [30] . Additionally, many groups have demonstrated that GPER activation is also tumor suppressive in cancers that are classically considered sex hormone responsive, including endometrial cancer, ovarian cancer, prostate cancer, and Leydig cell tumors [31] [32] [33] [34] [35] . Although GPER signaling was originally thought to be tumor promoting in some breast cancer models [36] , subsequent reports show that GPER signaling inhibits breast cancer [37] [38] [39] . Consistent with this, recent studies showed that the presence of GPER protein in human breast cancer tissue correlates with longer survival [40] . In summary, many independent groups have demonstrated that GPER activation may be a therapeutically useful mechanism for a wide range of cancer types.
Linnaeus Therapeutics is currently running NCI clinical trial (NCT04130516) using GPER agonist, LNS8801, as monotherapy and in combination with the immune checkpoint inhibitor, pembrolizumab, for the treatment of multiple solid tumor malignancies. Activation of GPER with LNS8801 has demonstrated efficacy in humans in cutaneous melanoma, uveal melanoma, lung cancer, neuroendocrine cancer, colorectal cancer, and other PD-1 inhibitor refractory cancers [41] [42] [43] .
Estradiol produces cell proliferation in both normal and malignant breast epithelial tissue. [44] [45] However, GPER knockout mice show no overt mammary phenotype, unlike ERα knockout mice, but similarly to ERβ knockout mice. [44] This indicates that although GPER and ERβ play a modulatory role in breast development, ERα is the main receptor responsible for estrogen-mediated breast tissue growth. [44] GPER is expressed in germ cells and has been found to be essential for male fertility, specifically, in spermatogenesis. [46] [47] [48] [49] GPER has been found to modulate gonadotropin-releasing hormone (GnRH) secretion in the hypothalamic-pituitary-gonadal (HPG) axis. [49]
GPER is expressed in the blood vessel endothelium and is responsible for vasodilation and as a result, blood pressure lowering effects of 17β-estradiol. [50] GPER also regulates components of the renin–angiotensin system, which also controls blood pressure, [51] [52] and is required for superoxide-mediated cardiovascular function and aging. [53]
GPER and ERα, but not ERβ, have been found to mediate the antidepressant-like effects of estradiol. [54] [55] [56] Contrarily, activation of GPER has been found to be anxiogenic in mice, while activation of ERβ has been found to be anxiolytic. [57] 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. [56] [58] It is speculated that activation of GPER may be the mechanism by which estradiol mediates rapid effects on the oxytocin system, [56] [58] for instance, rapidly increasing oxytocin receptor expression. [59] 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. [59] 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. [60] [61]
Female GPER knockout mice display hyperglycemia and impaired glucose tolerance, reduced body growth, and increased blood pressure. [62] Male GPER knockout mice are observed to have increased growth, body fat, insulin resistance and glucose intolerance, dyslipidemia, increased osteoblast function (mineralization), resulting in higher bone mineral density and trabecular bone volume, and persistent growth plate activity resulting in longer bones. [63] [64] The GPER-selective agonist G-1 shows therapeutic efficacy in mouse models of obesity and diabetes. [65]
GPER is broadly expressed on the nervous system, and GPER activation promotes beneficial effects in several brain disorders. [66] A study suggests that GPER levels were significantly lower in children with ADHD compared to controls. [67]
Estrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal activity: estrone (E1), estradiol (E2), and estriol (E3). Estradiol, an estrane, is the most potent and prevalent. Another estrogen called estetrol (E4) is produced only during pregnancy.
Estradiol (E2), also spelled oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of female reproductive cycles such as estrous and menstrual cycles. Estradiol is responsible for the development of female secondary sexual characteristics such as the breasts, widening of the hips and a female pattern of fat distribution. It is also important in the development and maintenance of female reproductive tissues such as the mammary glands, uterus and vagina during puberty, adulthood and pregnancy. It also has important effects in many other tissues including bone, fat, skin, liver, and the brain.
Estriol (E3), also spelled oestriol, is a steroid, a weak estrogen, and a minor female sex hormone. It is one of three major endogenous estrogens, the others being estradiol and estrone. Levels of estriol in women who are not pregnant are almost undetectable. However, during pregnancy, estriol is synthesized in very high quantities by the placenta and is the most produced estrogen in the body by far, although circulating levels of estriol are similar to those of other estrogens due to a relatively high rate of metabolism and excretion. Relative to estradiol, both estriol and estrone have far weaker activity as estrogens.
Steroid hormone receptors are found in the nucleus, cytosol, and also on the plasma membrane of target cells. They are generally intracellular receptors and initiate signal transduction for steroid hormones which lead to changes in gene expression over a time period of hours to days. The best studied steroid hormone receptors are members of the nuclear receptor subfamily 3 (NR3) that include receptors for estrogen and 3-ketosteroids. In addition to nuclear receptors, several G protein-coupled receptors and ion channels act as cell surface receptors for certain steroid hormones.
Fulvestrant, sold under the brand name Faslodex among others, is an antiestrogenic medication used to treat hormone receptor (HR)-positive metastatic breast cancer in postmenopausal women with disease progression as well as HR-positive, HER2-negative advanced breast cancer in combination with abemaciclib or palbociclib in women with disease progression after endocrine therapy. It is given by injection into a muscle.
2-Methoxyestradiol is a natural metabolite of estradiol and 2-hydroxyestradiol (2-OHE2). It is specifically the 2-methyl ether of 2-hydroxyestradiol. 2-Methoxyestradiol prevents the formation of new blood vessels that tumors need in order to grow (angiogenesis), hence it is an angiogenesis inhibitor. It also acts as a vasodilator and induces apoptosis in some cancer cell lines. 2-Methoxyestradiol is derived from estradiol, although it interacts poorly with the estrogen receptors. However, it retains activity as a high-affinity agonist of the G protein-coupled estrogen receptor (GPER).
Estrogen receptors (ERs) are a group of proteins found inside cells. They are receptors that are activated by the hormone estrogen (17β-estradiol). Two classes of ER exist: nuclear estrogen receptors, which are members of the nuclear receptor family of intracellular receptors, and membrane estrogen receptors (mERs), which are mostly G protein-coupled receptors. This article refers to the former (ER).
Genistein (C15H10O5) is a naturally occurring compound that structurally belongs to a class of compounds known as isoflavones. It is described as an angiogenesis inhibitor and a phytoestrogen.
Estrogen receptor beta (ERβ) also known as NR3A2 is one of two main types of estrogen receptor—a nuclear receptor which is activated by the sex hormone estrogen. In humans ERβ is encoded by the ESR2 gene.
Antiestrogens, also known as estrogen antagonists or estrogen blockers, are a class of drugs which prevent estrogens like estradiol from mediating their biological effects in the body. They act by blocking the estrogen receptor (ER) and/or inhibiting or suppressing estrogen production. Antiestrogens are one of three types of sex hormone antagonists, the others being antiandrogens and antiprogestogens. Antiestrogens are commonly used to stop steroid hormones, estrogen, from binding to the estrogen receptors leading to the decrease of estrogen levels. Decreased levels of estrogen can lead to complications in sexual development. Antiandrogens are sex hormone antagonists which are able to lower the production and the effects that testosterone can have on female bodies.
Afimoxifene, also known as 4-hydroxytamoxifen (4-OHT) and by its tentative brand name TamoGel, is a selective estrogen receptor modulator (SERM) of the triphenylethylene group and an active metabolite of tamoxifen. The drug is under development under the tentative brand name TamoGel as a topical gel for the treatment of hyperplasia of the breast. It has completed a phase II clinical trial for cyclical mastalgia, but further studies are required before afimoxifene can be approved for this indication and marketed.
Estetrol (E4), or oestetrol, is one of the four natural estrogenic steroid hormones found in humans, along with estrone (E1), estradiol (E2), and estriol (E3). Estetrol is a major estrogen in the body. In contrast to estrone and estradiol, estetrol is a native estrogen of fetal life. Estetrol is produced exclusively by the fetal liver and is found in detectable levels only during pregnancy, with relatively high levels in the fetus and lower levels in the maternal circulation.
4-Methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP) is a metabolite of bisphenol A (BPA). MBP has potent estrogenic activity in vitro and in vivo, up to thousandfold stronger than BPA. It may also play a role in neuronal cell apoptosis and may increase risk for several forms of cancer.
Neurodegenerative diseases can disrupt the normal human homeostasis and result in abnormal estrogen levels. For example, neurodegenerative diseases can cause different physiological effects in males and females. In particular, estrogen studies have revealed complex interactions with neurodegenerative diseases. Estrogen was initially proposed to be a possible treatment for certain types of neurodegenerative diseases but a plethora of harmful side effects such as increased susceptibility to breast cancer and coronary heart disease overshadowed any beneficial outcomes. On the other hand, Estrogen Replacement Therapy has shown some positive effects with postmenopausal women. Estrogen and estrogen-like molecules form a large family of potentially beneficial alternatives that can have dramatic effects on human homeostasis and disease. Subsequently, large-scale efforts were initiated to screen for useful estrogen family molecules. Furthermore, scientists discovered new ways to synthesize estrogen-like compounds that can avoid many side effects.
Membrane estrogen receptors (mERs) are a group of receptors which bind estrogen. Unlike nuclear estrogen receptors, which mediate their effects via slower genomic mechanisms, mERs are cell surface receptors that rapidly alter cell signaling via modulation of intracellular signaling cascades.
The Gq-coupled membrane estrogen receptor (Gq-mER) is a G protein-coupled receptor present in the hypothalamus that has not yet been cloned. It is a membrane-associated receptor that is Gq-coupled to a phospholipase C–protein kinase C–protein kinase A (PLC–PKC–PKA) pathway. The receptor has been implicated in the control of energy homeostasis. Gq-mER is bound and activated by estradiol, and is a putative membrane estrogen receptor (mER). A nonsteroidal diphenylacrylamide derivative, STX, which is structurally related to 4-hydroxytamoxifen (afimoxifene), is an agonist of the receptor with greater potency than estradiol that has been discovered. Fulvestrant (ICI-182,780) has been identified as an antagonist of Gq-mER, but is not selective.
2-Hydroxyestradiol (2-OHE2), also known as estra-1,3,5(10)-triene-2,3,17β-triol, is an endogenous steroid, catechol estrogen, and metabolite of estradiol, as well as a positional isomer of estriol.
7β-Hydroxyepiandrosterone (7β-OH-EPIA), also known as 5α-androstan-3β,7β-diol-17-one, is an endogenous androgen, estrogen, and neurosteroid that is produced from dehydroepiandrosterone and epiandrosterone. It has neuroprotective effects and, along with 7α-hydroxyepiandrosterone, may mediate the neuroprotective effects of DHEA. 7β-OH-EPIA may act as a highly potent antagonist of the G protein-coupled estrogen receptor (GPER).
Estradiol glucuronide, or estradiol 17β-D-glucuronide, is a conjugated metabolite of estradiol. It is formed from estradiol in the liver by UDP-glucuronyltransferase via attachment of glucuronic acid and is eventually excreted in the urine by the kidneys. It has much higher water solubility than does estradiol. Glucuronides are the most abundant estrogen conjugates.
Endocrine therapy is a common treatment for estrogen receptor positive breast cancer. However, resistance to this therapy can develop, leading to relapse and progression of disease. This highlights the need for new strategies to combat this resistance.
Nicotinic acid, also known as niacin, is the water soluble vitamin B3 used for decades for the treatment of dyslipidemic diseases. Its action is mainly mediated by the G protein-coupled receptor (GPR) 109A; however, certain regulatory effects on lipid levels occur in a GPR109A-independent manner. The amide form of nicotinic acid, named nicotinamide, acts as a vitamin although neither activates the GPR109A nor exhibits the pharmacological properties of nicotinic acid. In the present study, we demonstrate for the first time that nicotinic acid and nicotinamide bind to and activate the GPER-mediated signalling in breast cancer cells and cancer-associated fibroblasts (CAFs)
{{cite journal}}: Cite journal requires |journal= (help)The development of the GPER-selective agonist G-114 has facilitated studies that demonstrate GPER activation induces acute vasodilation and lowers blood pressure in rodents. We18 and others17,19 have shown that acute GPER-mediated vasodilator effects are at least partly endothelium- and NO-dependent.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.