G protein-coupled estrogen receptor 1 (GPER), also known asG protein-coupled receptor 30 (GPR30), is aprotein that in humans is encoded by theGPERgene.[5] GPER binds to and is activated by the female sex hormoneestradiol and is responsible for some of the rapid effects that estradiol has on cells.[6]
The classicalestrogen receptors first characterized in 1958[7] are water-soluble proteins located in theinterior of cells that are activated byestrogenenic hormones such as estradiol and several of itsmetabolites such asestrone orestriol. These proteins belong to thenuclear hormone receptor class oftranscription factors that regulategene 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 theG 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 theendoplasmic reticulum.[9][8]
This protein is a member of therhodopsin-like family ofG 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 ofphosphatidylinositol (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 thehypothalamus,pituitary gland,adrenal medulla,kidney medulla and developing follicles of theovary.[22]
GPER expression has been studied in cancer using immunohistochemical and transcriptomic approaches, and has been detected in: colon, lung, melanoma, pancreatic, breast,[23] ovarian,[24] and testicular cancer.[25]
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.[26][27][28][29] 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.[30][31][32][33][34] Although GPER signaling was originally thought to be tumor promoting in some breast cancer models,[35] subsequent reports show that GPER signaling inhibits breast cancer.[36][37][38] Consistent with this, recent studies showed that the presence of GPER protein in human breast cancer tissue correlates with longer survival.[39] 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.[40][41][42]
GPER is expressed in the blood vesselendothelium and is responsible forvasodilation and as a result, blood pressure lowering effects ofestradiol.[49] GPER also regulates components of therenin–angiotensin system, which also controls blood pressure,[50][51] and is required for superoxide-mediated cardiovascular function and aging.[52]
GPER and ERα, but not ERβ, have been found to mediate theantidepressant-like effects ofestradiol.[53][54][55] Contrarily, activation of GPER has been found to beanxiogenic in mice, while activation of ERβ has been found to beanxiolytic.[56] There is a highexpression of GPER, as well as ERβ, inoxytocin neurons in various parts of thehypothalamus, including theparaventricular nucleus and thesupraoptic nucleus.[55][57] It is speculated that activation of GPER may be the mechanism by which estradiol mediates rapid effects on the oxytocin system,[55][57] for instance, rapidly increasingoxytocin receptor expression.[58] Estradiol has also been found to increase oxytocin levels and release in themedial preoptic area and medial basal hypothalamus, actions that may be mediated by activation of GPER and/or ERβ.[58] Estradiol, as well astamoxifen andfulvestrant, have been found to rapidly inducelordosis through activation of GPER in the arcuate nucleus of the hypothalamus of female rats.[59][60]
Female GPERknockout mice displayhyperglycemia and impairedglucose tolerance, reduced body growth, and increasedblood pressure.[61] Male GPER knockout mice are observed to have increased growth, body fat, insulin resistance and glucose intolerance, dyslipidemia, increasedosteoblast function (mineralization), resulting in higher bone mineral density andtrabecular bone volume, and persistent growth plate activity resulting in longer bones.[62][63] The GPER-selective agonist G-1 shows therapeutic efficacy in mouse models of obesity and diabetes.[64]
GPER is broadly expressed on the nervous system, and GPER activation promotes beneficial effects in several brain disorders.[65] A study suggests that GPER levels were significantly lower in children with ADHD compared to controls.[66]
^Filardo EJ, Thomas P (October 2005). "GPR30: a seven-transmembrane-spanning estrogen receptor that triggers EGF release".Trends in Endocrinology and Metabolism.16 (8):362–367.doi:10.1016/j.tem.2005.08.005.PMID16125968.S2CID33801811.
^Cheng SB, Dong J, Pang Y, LaRocca J, Hixon M, Thomas P, et al. (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):950–959.doi:10.1016/j.mce.2013.11.005.PMID24239983.S2CID28896943.
^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".Cellular Signalling.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".Journal of Cellular Physiology.225 (3):792–800.doi:10.1002/jcp.22284.PMID20568229.S2CID24889239.
^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):207–212.doi:10.1038/nchembio775.PMID16520733.S2CID2364534.
^Sjöström M, Hartman L, Grabau D, Fornander T, Malmström P, Nordenskjöld B, et al. (May 2014). "Lack of G protein-coupled estrogen receptor (GPER) in the plasma membrane is associated with excellent long-term prognosis in breast cancer".Breast Cancer Research and Treatment.145 (1):61–71.doi:10.1007/s10549-014-2936-4.PMID24715381.S2CID10593826.
^Zhu G, Huang Y, Wu C, Wei D, Shi Y (August 2016). "Activation of G-Protein-Coupled Estrogen Receptor Inhibits the Migration of Human Nonsmall Cell Lung Cancer Cells via IKK-β/NF-κB Signals".DNA and Cell Biology.35 (8):434–442.doi:10.1089/dna.2016.3235.PMID27082459.
^Fábián M, Rencz F, Krenács T, Brodszky V, Hársing J, Németh K, et al. (September 2017). "Expression of G protein-coupled oestrogen receptor in melanoma and in pregnancy-associated melanoma".Journal of the European Academy of Dermatology and Venereology.31 (9):1453–1461.doi:10.1111/jdv.14304.PMID28467693.
^Skrzypczak M, Schüler S, Lattrich C, Ignatov A, Ortmann O, Treeck O (November 2013). "G protein-coupled estrogen receptor (GPER) expression in endometrial adenocarcinoma and effect of agonist G-1 on growth of endometrial adenocarcinoma cell lines".Steroids.78 (11):1087–1091.doi:10.1016/j.steroids.2013.07.007.PMID23921077.
^Rodon J, Chaney M, Cohen J, Garyantes T, Lin J, Lorusso P, et al. (November 2022). "759 Phase 1b study of LNS8801 in combination with pembrolizumab in patients with secondary resistance to immune checkpoint inhibitors".Regular and Young Investigator Award Abstracts. BMJ Publishing Group Ltd: A790.doi:10.1136/jitc-2022-sitc2022.0759.
^Carreau S, Bouraima-Lelong H, Delalande C (November 2011). "Estrogens: new players in spermatogenesis".Reproductive Biology.11 (3):174–193.doi:10.1016/s1642-431x(12)60065-5.PMID22139333.
^Carreau S, Bois C, Zanatta L, Silva FR, Bouraima-Lelong H, Delalande C (October 2011). "Estrogen signaling in testicular cells".Life Sciences.89 (15–16):584–587.doi:10.1016/j.lfs.2011.06.004.PMID21703280.
^Carreau S, Bouraima-Lelong H, Delalande C (June 2012). "Estrogen, a female hormone involved in spermatogenesis".Advances in Medical Sciences.57 (1):31–36.doi:10.2478/v10039-012-0005-y.PMID22440937.
^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.doi:10.1016/j.phrs.2013.02.008.PMID23466742.
^Estrada-Camarena E, López-Rubalcava C, Vega-Rivera N, Récamier-Carballo S, Fernández-Guasti A (September 2010). "Antidepressant effects of estrogens: a basic approximation".Behavioural Pharmacology.21 (5–6):451–464.doi:10.1097/FBP.0b013e32833db7e9.PMID20700047.S2CID205595404.
^Roque C, Mendes-Oliveira J, Duarte-Chendo C, Baltazar G (October 2019). "The role of G protein-coupled estrogen receptor 1 on neurological disorders".Frontiers in Neuroendocrinology.55 100786.doi:10.1016/j.yfrne.2019.100786.PMID31513775.S2CID202043731.
