GPER explained

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.[1] 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.[2]

Discovery

The classical estrogen receptors first characterized in 1958[3] 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.[4] 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.[4]

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.[5] [6] [7] [8] Although potentially involved in signaling by aldosterone, GPER does not show any detectable binding towards aldosterone.[9] [10] Niacin and nicotinamide bind to the receptor in vitro with very low affinity.[11] [12] CCL18 has been identified as an endogenous antagonist of the GPER.[13] GPER-selective ligands (that do not bind the classical estrogen receptors) include the agonist G-1[14] and the antagonists G15[15] and G36.[16]

Agonists

Antagonists

Unknown

Non-ligand

Function

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.[5] This protein therefore plays a role in the rapid nongenomic signaling events widely observed following stimulation of cells and tissues with estradiol.[17] 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.[18]

Role in cancer

GPER expression has been studied in cancer using immunohistochemical and transcriptomic approaches, and has been detected in: colon, lung, melanoma, pancreatic, breast,[19] ovarian,[20] and testicular cancer.[21]

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.[22] [23] [24] [25] 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.[26] [27] [28] [29] [30] Although GPER signaling was originally thought to be tumor promoting in some breast cancer models,[31] subsequent reports show that GPER signaling inhibits breast cancer.[32] [33] [34] Consistent with this, recent studies showed that the presence of GPER protein in human breast cancer tissue correlates with longer survival.[35] 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.[36] [37] [38]

Role in normal tissues

Reproductive tissue

Estradiol produces cell proliferation in both normal and malignant breast epithelial tissue.[39] [40] However, GPER knockout mice show no overt mammary phenotype, unlike ERα knockout mice, but similarly to ERβ knockout mice. 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. GPER is expressed in germ cells and has been found to be essential for male fertility, specifically, in spermatogenesis.[41] [42] [43] [44] GPER has been found to modulate gonadotropin-releasing hormone (GnRH) secretion in the hypothalamic-pituitary-gonadal (HPG) axis.

Cardiovascular effects

GPER is expressed in the blood vessel endothelium and is responsible for vasodilation and as a result, blood pressure lowering effects of 17β-estradiol.[45] GPER also regulates components of the renin–angiotensin system, which also controls blood pressure,[46] [47] and is required for superoxide-mediated cardiovascular function and aging.[48]

Central nervous system activity

GPER and ERα, but not ERβ, have been found to mediate the antidepressant-like effects of estradiol.[49] [50] [51] Contrarily, activation of GPER has been found to be anxiogenic in mice, while activation of ERβ has been found to be anxiolytic.[52] 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.[53] 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.[54] 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.[55] [56]

Metabolic roles

Female GPER knockout mice display hyperglycemia and impaired glucose tolerance, reduced body growth, and increased blood pressure.[57] 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.[58] [59] The GPER-selective agonist G-1 shows therapeutic efficacy in mouse models of obesity and diabetes.[60]

Role in neurological disorders

GPER is broadly expressed on the nervous system, and GPER activation promotes beneficial effects in several brain disorders.[61] A study suggests that GPER levels were significantly lower in children with ADHD compared to controls.[62]

See also

External links

Notes and References

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  2. Prossnitz ER, Arterburn JB . International Union of Basic and Clinical Pharmacology. XCVII. G Protein-Coupled Estrogen Receptor and Its Pharmacologic Modulators . Pharmacological Reviews . 67 . 3 . 505–540 . July 2015 . 26023144 . 4485017 . 10.1124/pr.114.009712 .
  3. Jensen E . A conversation with Elwood Jensen. Interview by David D. Moore . Annual Review of Physiology . 74 . 1–11 . 2012 . 21888507 . 10.1146/annurev-physiol-020911-153327 . 196618575 . free .
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  5. Revankar CM, Cimino DF, Sklar LA, Arterburn JB, Prossnitz ER . A transmembrane intracellular estrogen receptor mediates rapid cell signaling . Science . 307 . 5715 . 1625–1630 . March 2005 . 15705806 . 10.1126/science.1106943 . 15789136 . free . 2005Sci...307.1625R .
  6. Filardo EJ, Thomas P . GPR30: a seven-transmembrane-spanning estrogen receptor that triggers EGF release . Trends in Endocrinology and Metabolism . 16 . 8 . 362–367 . October 2005 . 16125968 . 10.1016/j.tem.2005.08.005 . 33801811 .
  7. Manavathi B, Kumar R . Steering estrogen signals from the plasma membrane to the nucleus: two sides of the coin . Journal of Cellular Physiology . 207 . 3 . 594–604 . June 2006 . 16270355 . 10.1002/jcp.20551 . 27712910 . free .
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  9. Wendler A, Albrecht C, Wehling M . Nongenomic actions of aldosterone and progesterone revisited . Steroids . 77 . 10 . 1002–1006 . August 2012 . 22285849 . 10.1016/j.steroids.2011.12.023 . 28968323 .
  10. Cheng SB, Dong J, Pang Y, LaRocca J, Hixon M, Thomas P, Filardo EJ . 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 . February 2014 . 24239983 . 10.1016/j.mce.2013.11.005 . 28896943 .
  11. Santolla MF, De Francesco EM, Lappano R, Rosano C, Abonante S, Maggiolini M . Niacin activates the G protein estrogen receptor (GPER)-mediated signalling . Cellular Signalling . 26 . 7 . 1466–1475 . July 2014 . 24662263 . 10.1016/j.cellsig.2014.03.011 . 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) .
  12. Barton M . Not lost in translation: Emerging clinical importance of the G protein-coupled estrogen receptor GPER . Steroids . 111 . 37–45 . July 2016 . 26921679 . 10.1016/j.steroids.2016.02.016 . free .
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  14. Bologa CG, Revankar CM, Young SM, Edwards BS, Arterburn JB, Kiselyov AS, Parker MA, Tkachenko SE, Savchuck NP, Sklar LA, Oprea TI, Prossnitz ER . Virtual and biomolecular screening converge on a selective agonist for GPR30 . Nature Chemical Biology . 2 . 4 . 207–212 . April 2006 . 16520733 . 10.1038/nchembio775 . 2364534 .
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  16. Dennis MK, Field AS, Burai R, Ramesh C, Petrie WK, Bologa CG, Oprea TI, Yamaguchi Y, Hayashi S, Sklar LA, Hathaway HJ, Arterburn JB, Prossnitz ER . Identification of a GPER/GPR30 antagonist with improved estrogen receptor counterselectivity . The Journal of Steroid Biochemistry and Molecular Biology . 127 . 3–5 . 358–366 . November 2011 . 21782022 . 3220788 . 10.1016/j.jsbmb.2011.07.002 .
  17. Web site: Entrez Gene: GPR30 G protein-coupled receptor 30.
  18. Hazell GG, Yao ST, Roper JA, Prossnitz ER, O'Carroll AM, Lolait SJ . Localisation of GPR30, a novel G protein-coupled oestrogen receptor, suggests multiple functions in rodent brain and peripheral tissues . The Journal of Endocrinology . 202 . 2 . 223–236 . August 2009 . 19420011 . 2710976 . 10.1677/JOE-09-0066 .
  19. Sjöström M, Hartman L, Grabau D, Fornander T, Malmström P, Nordenskjöld B, Sgroi DC, Skoog L, Stål O, Leeb-Lundberg LM, Fernö M . 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 . May 2014 . 24715381 . 10.1007/s10549-014-2936-4 . 10593826 .
  20. Smith HO, Arias-Pulido H, Kuo DY, Howard T, Qualls CR, Lee SJ, Verschraegen CF, Hathaway HJ, Joste NE, Prossnitz ER . GPR30 predicts poor survival for ovarian cancer . Gynecologic Oncology . 114 . 3 . 465–471 . September 2009 . 19501895 . 2921775 . 10.1016/j.ygyno.2009.05.015 .
  21. Chevalier N, Vega A, Bouskine A, Siddeek B, Michiels JF, Chevallier D, Fénichel P . GPR30, the non-classical membrane G protein related estrogen receptor, is overexpressed in human seminoma and promotes seminoma cell proliferation . PLOS ONE . 7 . 4 . e34672 . 2012 . 22496838 . 3319601 . 10.1371/journal.pone.0034672 . 2012PLoSO...734672C . free .
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  23. Liu Q, Chen Z, Jiang G, Zhou Y, Yang X, Huang H, Liu H, Du J, Wang H . Epigenetic down regulation of G protein-coupled estrogen receptor (GPER) functions as a tumor suppressor in colorectal cancer . Molecular Cancer . 16 . 1 . 87 . May 2017 . 28476123 . 5418684 . 10.1186/s12943-017-0654-3 . free .
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  28. Skrzypczak M, Schüler S, Lattrich C, Ignatov A, Ortmann O, Treeck O . 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 . November 2013 . 23921077 . 10.1016/j.steroids.2013.07.007 .
  29. Chimento A, Casaburi I, Bartucci M, Patrizii M, Dattilo R, Avena P, Andò S, Pezzi V, Sirianni R . Selective GPER activation decreases proliferation and activates apoptosis in tumor Leydig cells . Cell Death & Disease . 4 . 8 . e747 . August 2013 . 23907461 . 3763437 . 10.1038/cddis.2013.275 .
  30. Natale CA, Li J, Pitarresi JR, Norgard RJ, Dentchev T, Capell BC, Seykora JT, Stanger BZ, Ridky TW . Pharmacologic Activation of the G Protein-Coupled Estrogen Receptor Inhibits Pancreatic Ductal Adenocarcinoma . Cellular and Molecular Gastroenterology and Hepatology . 10 . 4 . 868–880.e1 . 2018-07-09 . 32376419 . 10.1101/365668 .
  31. Lappano R, Pisano A, Maggiolini M . GPER Function in Breast Cancer: An Overview . Frontiers in Endocrinology . 5 . 66 . 2014-05-06 . 24834064 . 4018520 . 10.3389/fendo.2014.00066 . free .
  32. Wei W, Chen ZJ, Zhang KS, Yang XL, Wu YM, Chen XH, Huang HB, Liu HL, Cai SH, Du J, Wang HS . The activation of G protein-coupled receptor 30 (GPR30) inhibits proliferation of estrogen receptor-negative breast cancer cells in vitro and in vivo . Cell Death & Disease . 5 . 10 . e1428 . October 2014 . 25275589 . 4649509 . 10.1038/cddis.2014.398 .
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  39. Scaling AL, Prossnitz ER, Hathaway HJ . GPER mediates estrogen-induced signaling and proliferation in human breast epithelial cells and normal and malignant breast . Hormones & Cancer . 5 . 3 . 146–160 . June 2014 . 24718936 . 4091989 . 10.1007/s12672-014-0174-1 .
  40. Lappano R, Pisano A, Maggiolini M . GPER Function in Breast Cancer: An Overview . Frontiers in Endocrinology . 5 . 66 . 2014 . 24834064 . 4018520 . 10.3389/fendo.2014.00066 . free . review .
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