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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.

GPER1
Identifiers
AliasesGPER1, Gper1, 6330420K13Rik, CMKRL2, Ceprl, FEG-1, GPCR-Br, Gper, Gpr30, CEPR, DRY12, LERGU, LERGU2, LyGPR, mER, G protein-coupled estrogen receptor 1
External IDsMGI: 1924104 HomoloGene: 15855 GeneCards: GPER1
Gene location (Human)
Chromosome 7 (human)
Chr.Chromosome 7 (human)[1]
Chromosome 7 (human)
Genomic location for GPER1
Genomic location for GPER1
Band7p22.3Start1,082,208 bp[1]
End1,093,815 bp[1]
RNA expression pattern
PBB GE GPR30 211829 s at fs.png

PBB GE GPR30 210640 s at fs.png
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001031682
NM_001039966
NM_001098201
NM_001505

NM_029771

RefSeq (protein)

NP_001035055
NP_001091671
NP_001496

NP_084047

Location (UCSC)Chr 7: 1.08 – 1.09 MbChr 5: 139.42 – 139.43 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Contents

DiscoveryEdit

The classical estrogen receptors first characterized in 1958[6] 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.[7] 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). Unlike the other members of the GPCR family, which reside in the outer membrane of cells, GPER is localized in the endoplasmic reticulum.[7]

LigandsEdit

GPER binds estradiol though not other endogenous estrogens, such as estrone or estriol, nor for other endogenous steroids, including progesterone, testosterone, and cortisol.[8][9][10][11] Although potentially involved in signaling by aldosterone, GPER does not show any detectable binding towards aldosterone.[12][13] Niacin and nicotinamide bind to the receptor in vitro with very low affinity.[14][15] CCL18 has been identified as an endogenous antagonist of the GPER.[16]

FunctionEdit

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 endoplasmic reticulum. The protein binds estradiol, resulting in intracellular calcium mobilization and synthesis of phosphatidylinositol (3,4,5)-trisphosphate in the nucleus.[8] 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]

Animal studiesEdit

Reproductive tissueEdit

GPER is expressed in the breasts, and activation by estradiol produces cell proliferation in both normal and malignant breast epithelial tissue.[19][20] However, GPER knockout mice show no overt mammary phenotype, unlike ERα knockout mice, but similarly to ERβ knockout mice.[19] 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.[19] GPER is expressed in germ cells and has been found to be essential for male fertility, specifically, in spermatogenesis.[21][22][23][24] GPER has been found to modulate gonadotropin-releasing hormone (GnRH) secretion in the hypothalamic-pituitary-gonadal (HPG) axis.[24]

Cardiovascular effectsEdit

GPER is expressed in the blood vessel endothelium and is responsible for vasodilation and as a result, blood pressure lowering effects of 17β-estradiol.[25] GPER also regulates components of the renin–angiotensin system, which also controls blood pressure,[26][27] and is required for superoxide-mediated cardiovascular function and aging.[28]

Central nervous system activityEdit

GPER and ERα, but not ERβ, have been found to mediate the antidepressant-like effects of estradiol.[29][30][31] Contrarily, activation of GPER has been found to be anxiogenic in mice, while activation of ERβ has been found to be anxiolytic.[32] 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.[31][33] It is speculated that activation of GPER may be the mechanism by which estradiol mediates rapid effects on the oxytocin system,[31][33] for instance, rapidly increasing oxytocin receptor expression.[34] 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.[34] 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.[35][36]

Metabolic rolesEdit

Female GPER knockout mice display hyperglycemia and impaired glucose tolerance, reduced body growth, and increased blood pressure.[37] 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.[38][39]

Role in cancerEdit

Although GPER signaling was originally thought to be tumor-promoting in breast cancer,[40] subsequent reports suggest that nonclassical estrogen signaling is tumor suppressive in breast cancer.[41][42][43] 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.[44] In line with findings in breast cancer, GPER signaling has also been shown to be tumor suppressive in adrenocortical carcinoma,[45] colorectal cancer,[46] endometrial cancer,[47] Leydig cell tumors,[48] non-small cell lung cancer,[49] gastric cancer,[50] liver cancer,[51] melanoma,[52] osteosarcoma,[53] ovarian cancer,[54] and prostate cancer.[55] 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.

See alsoEdit

ReferencesEdit

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  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000053647 - Ensembl, May 2017
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  4. ^ "Mouse PubMed Reference:".
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  6. ^ Jensen E (2012). "A conversation with Elwood Jensen. Interview by David D. Moore". Annual Review of Physiology. 74: 1–11. doi:10.1146/annurev-physiol-020911-153327. PMID 21888507.
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  9. ^ 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. PMID 16125968.
  10. ^ Manavathi B, Kumar R (June 2006). "Steering estrogen signals from the plasma membrane to the nucleus: two sides of the coin". Journal of Cellular Physiology. 207 (3): 594–604. doi:10.1002/jcp.20551. PMID 16270355.
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  12. ^ Wendler A, Albrecht C, Wehling M (August 2012). "Nongenomic actions of aldosterone and progesterone revisited". Steroids. 77 (10): 1002–6. doi:10.1016/j.steroids.2011.12.023. PMID 22285849.
  13. ^ 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. PMID 24239983.
  14. ^ 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. PMID 24662263. 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)
  15. ^ Barton M (February 2016). "Not lost in translation: Emerging clinical importance of the G protein-coupled estrogen receptor GPER". Steroids. 111: 37–45. doi:10.1016/j.steroids.2016.02.016. PMID 26921679.
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  26. ^ Lindsey SH, Chappell MC (December 2011). "Evidence that the G protein-coupled membrane receptor GPR30 contributes to the cardiovascular actions of estrogen". Gender Medicine. 8 (6): 343–54. doi:10.1016/j.genm.2011.10.004. PMC 3240864. PMID 22153880.
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  39. ^ Sharma G, Hu C, Brigman JL, Zhu G, Hathaway HJ, Prossnitz ER (November 2013). "GPER deficiency in male mice results in insulin resistance, dyslipidemia, and a proinflammatory state". Endocrinology. 154 (11): 4136–45. doi:10.1210/en.2013-1357. PMC 3800768. PMID 23970785.
  40. ^ Lappano R, Pisano A, Maggiolini M (2014). "GPER Function in Breast Cancer: An Overview". Frontiers in Endocrinology. 5: 66. doi:10.3389/fendo.2014.00066. PMC 4018520. PMID 24834064.
  41. ^ Wei W, Chen ZJ, Zhang KS, Yang XL, Wu YM, Chen XH, et al. (October 2014). "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. doi:10.1038/cddis.2014.398. PMC 4649509. PMID 25275589.
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  44. ^ Martin SG, Lebot MN, Sukkarn B, Ball G, Green AR, Rakha EA, et al. (May 2018). "Low expression of G protein-coupled oestrogen receptor 1 (GPER) is associated with adverse survival of breast cancer patients". Oncotarget. 9 (40): 25946–25956. doi:10.18632/oncotarget.25408. PMC 5995224. PMID 29899833.
  45. ^ Chimento A, Sirianni R, Casaburi I, Zolea F, Rizza P, Avena P, et al. (August 2015). "GPER agonist G-1 decreases adrenocortical carcinoma (ACC) cell growth in vitro and in vivo". Oncotarget. 6 (22): 19190–203. doi:10.18632/oncotarget.4241. PMID 26131713.
  46. ^ Liu Q, Chen Z, Jiang G, Zhou Y, Yang X, Huang H, et al. (May 2017). "Epigenetic down regulation of G protein-coupled estrogen receptor (GPER) functions as a tumor suppressor in colorectal cancer". Molecular Cancer. 16 (1): 87. doi:10.1186/s12943-017-0654-3. PMID 28476123.
  47. ^ 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): 1087–91. doi:10.1016/j.steroids.2013.07.007. PMID 23921077.
  48. ^ Chimento A, Casaburi I, Bartucci M, Patrizii M, Dattilo R, Avena P, et al. (August 2013). "Selective GPER activation decreases proliferation and activates apoptosis in tumor Leydig cells". Cell Death & Disease. 4 (8): e747. doi:10.1038/cddis.2013.275. PMID 23907461.
  49. ^ 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): 434–42. doi:10.1089/dna.2016.3235. PMID 27082459.
  50. ^ Tian S, Zhan N, Li R, Dong W (April 2019). "Downregulation of G Protein-Coupled Estrogen Receptor (GPER) is Associated with Reduced Prognosis in Patients with Gastric Cancer". Medical Science Monitor. 25: 3115–3126. doi:10.12659/MSM.913634. PMID 31028714.
  51. ^ Wei T, Chen W, Wen L, Zhang J, Zhang Q, Yang J, et al. (November 2016). "G protein-coupled estrogen receptor deficiency accelerates liver tumorigenesis by enhancing inflammation and fibrosis". Cancer Letters. 382 (2): 195–202. doi:10.1016/j.canlet.2016.08.012. PMID 27594673.
  52. ^ Ribeiro MP, Santos AE, Custódio JB (November 2017). "The activation of the G protein-coupled estrogen receptor (GPER) inhibits the proliferation of mouse melanoma K1735-M2 cells". Chemico-Biological Interactions. 277: 176–184. doi:10.1016/j.cbi.2017.09.017. PMID 28947257.
  53. ^ Wang Z, Chen X, Zhao Y, Jin Y, Zheng J (January 2019). "G-protein-coupled estrogen receptor suppresses the migration of osteosarcoma cells via post-translational regulation of Snail". Journal of Cancer Research and Clinical Oncology. 145 (1): 87–96. doi:10.1007/s00432-018-2768-4. PMID 30341688.
  54. ^ Ignatov T, Modl S, Thulig M, Weißenborn C, Treeck O, Ortmann O, et al. (July 2013). "GPER-1 acts as a tumor suppressor in ovarian cancer". Journal of Ovarian Research. 6 (1): 51. doi:10.1186/1757-2215-6-51. PMID 23849542.
  55. ^ Lam HM, Ouyang B, Chen J, Ying J, Wang J, Wu CL, et al. (2014). "Targeting GPR30 with G-1: a new therapeutic target for castration-resistant prostate cancer". Endocrine-Related Cancer. 21 (6): 903–14. doi:10.1530/ERC-14-0402. PMID 25287069.

External linksEdit

This article incorporates text from the United States National Library of Medicine, which is in the public domain.