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 GPERgene.[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]
Discovery
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]
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]
Role in cancer
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]
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]
Central nervous system activity
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]
Metabolic roles
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]
Role in neurological disorders
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]
^Filardo EJ, Thomas P (October 2005). "GPR30: a seven-transmembrane-spanning estrogen receptor that triggers EGF release". Trends in Endocrinology and Metabolism. 16 (8): 362–7.
doi:
10.1016/j.tem.2005.08.005.
PMID16125968.
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^Cheng SB, Dong J, Pang Y, LaRocca J, Hixon M, Thomas P, Filardo EJ (February 2014). "Anatomical location and redistribution of G protein-coupled estrogen receptor-1 during the estrus cycle in mouse kidney and specific binding to estrogens but not aldosterone". Molecular and Cellular Endocrinology. 382 (2): 950–9.
doi:
10.1016/j.mce.2013.11.005.
PMID24239983.
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^Santolla MF, De Francesco EM, Lappano R, Rosano C, Abonante S, Maggiolini M (July 2014). "Niacin activates the G protein estrogen receptor (GPER)-mediated signalling". Cell. Signal. 26 (7): 1466–1475.
doi:
10.1016/j.cellsig.2014.03.011.
PMID24662263. 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)
^Catusse J, Wollner S, Leick M, Schröttner P, Schraufstätter I, Burger M (November 2010). "Attenuation of CXCR4 responses by CCL18 in acute lymphocytic leukemia B cells". J. Cell. Physiol. 225 (3): 792–800.
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^Bologa CG, Revankar CM, Young SM, Edwards BS, Arterburn JB, Kiselyov AS, et al. (April 2006). "Virtual and biomolecular screening converge on a selective agonist for GPR30". Nature Chemical Biology. 2 (4): 207–12.
doi:
10.1038/nchembio775.
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^Meyer MR, Amann K, Field AS, Hu C, Hathaway HJ, Kanagy NL, Walker MK, Barton M, Prossnitz ER (February 2012).
"Deletion of G protein-coupled estrogen receptor increases endothelial vasoconstriction". Hypertension. 59 (2): 507–12.
doi:
10.1161/HYPERTENSIONAHA.111.184606.
PMC3266468.
PMID22203741. 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.
^Han G, Li F, Yu X, White RE (May 2013). "GPER: a novel target for non-genomic estrogen action in the cardiovascular system". Pharmacological Research. 71: 53–60.
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10.1016/j.phrs.2013.02.008.
PMID23466742.