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=== Reproductive tissue ===
=== Reproductive tissue ===
Estradiol produces [[cell proliferation]] in both normal and malignant [[breast]] [[epithelial tissue]].<ref name="pmid24718936">{{cite journal | vauthors = Scaling AL, Prossnitz ER, Hathaway HJ | title = GPER mediates estrogen-induced signaling and proliferation in human breast epithelial cells and normal and malignant breast | journal = Horm Cancer | volume = 5 | issue = 3 | pages = 146–60 | year = 2014 | pmid = 24718936 | pmc = 4091989 | doi = 10.1007/s12672-014-0174-1 }}</ref><ref name="Lappano_2014">{{cite journal | vauthors = Lappano R, Pisano A, Maggiolini M | title = GPER Function in Breast Cancer: An Overview | journal = Frontiers in Endocrinology | volume = 5 | pages = 66 | year = 2014 | pmid = 24834064 | pmc = 4018520 | doi = 10.3389/fendo.2014.00066 | department = review }}</ref> However, GPER [[knockout mouse|knockout mice]] show no overt [[mammary gland|mammary]] [[phenotype]], unlike [[estrogen receptor alpha|ERα]] knockout mice, but similarly to [[estrogen receptor beta|ERβ]] knockout mice.<ref name="pmid24718936" /> 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.<ref name="pmid24718936" /> GPER is expressed in [[germ cell]]s and has been found to be essential for male [[fertility]], specifically, in [[spermatogenesis]].<ref name="pmid22139333">{{cite journal | vauthors = Carreau S, Bouraima-Lelong H, Delalande C | title = Estrogens: new players in spermatogenesis | journal = Reprod Biol | volume = 11 | issue = 3 | pages = 174–93 | year = 2011 | pmid = 22139333 | doi = 10.1016/s1642-431x(12)60065-5 }}</ref><ref name="pmid21703280">{{cite journal | vauthors = Carreau S, Bois C, Zanatta L, Silva FR, Bouraima-Lelong H, Delalande C | title = Estrogen signaling in testicular cells | journal = Life Sci. | volume = 89 | issue = 15–16 | pages = 584–7 | year = 2011 | pmid = 21703280 | doi = 10.1016/j.lfs.2011.06.004 }}</ref><ref name="pmid22440937">{{cite journal | vauthors = Carreau S, Bouraima-Lelong H, Delalande C | title = Estrogen, a female hormone involved in spermatogenesis | journal = Adv Med Sci | volume = 57 | issue = 1 | pages = 31–6 | year = 2012 | pmid = 22440937 | doi = 10.2478/v10039-012-0005-y }}</ref><ref name="pmid24474947">{{cite journal | vauthors = Chimento A, Sirianni R, Casaburi I, Pezzi V | title = Role of estrogen receptors and g protein-coupled estrogen receptor in regulation of hypothalamus-pituitary-testis axis and spermatogenesis | journal = Front Endocrinol (Lausanne) | volume = 5 | pages = 1 | year = 2014 | pmid = 24474947 | pmc = 3893621 | doi = 10.3389/fendo.2014.00001 }}</ref> GPER has been found to modulate [[gonadotropin-releasing hormone]] (GnRH) secretion in the [[hypothalamic-pituitary-gonadal axis|hypothalamic-pituitary-gonadal]] (HPG) [[hypothalamic-pituitary-gonadal axis|axis]].<ref name="pmid24474947" />
Estradiol produces [[cell proliferation]] in both normal and malignant [[breast]] [[epithelial tissue]].<ref name="pmid24718936">{{cite journal | vauthors = Scaling AL, Prossnitz ER, Hathaway HJ | title = GPER mediates estrogen-induced signaling and proliferation in human breast epithelial cells and normal and malignant breast | journal = Horm Cancer | volume = 5 | issue = 3 | pages = 146–60 | year = 2014 | pmid = 24718936 | pmc = 4091989 | doi = 10.1007/s12672-014-0174-1 }}</ref><ref name="Lappano_2014">{{cite journal | vauthors = Lappano R, Pisano A, Maggiolini M | title = GPER Function in Breast Cancer: An Overview | journal = Frontiers in Endocrinology | volume = 5 | pages = 66 | year = 2014 | pmid = 24834064 | pmc = 4018520 | doi = 10.3389/fendo.2014.00066 | department = review | doi-access = free }}</ref> However, GPER [[knockout mouse|knockout mice]] show no overt [[mammary gland|mammary]] [[phenotype]], unlike [[estrogen receptor alpha|ERα]] knockout mice, but similarly to [[estrogen receptor beta|ERβ]] knockout mice.<ref name="pmid24718936" /> 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.<ref name="pmid24718936" /> GPER is expressed in [[germ cell]]s and has been found to be essential for male [[fertility]], specifically, in [[spermatogenesis]].<ref name="pmid22139333">{{cite journal | vauthors = Carreau S, Bouraima-Lelong H, Delalande C | title = Estrogens: new players in spermatogenesis | journal = Reprod Biol | volume = 11 | issue = 3 | pages = 174–93 | year = 2011 | pmid = 22139333 | doi = 10.1016/s1642-431x(12)60065-5 }}</ref><ref name="pmid21703280">{{cite journal | vauthors = Carreau S, Bois C, Zanatta L, Silva FR, Bouraima-Lelong H, Delalande C | title = Estrogen signaling in testicular cells | journal = Life Sci. | volume = 89 | issue = 15–16 | pages = 584–7 | year = 2011 | pmid = 21703280 | doi = 10.1016/j.lfs.2011.06.004 }}</ref><ref name="pmid22440937">{{cite journal | vauthors = Carreau S, Bouraima-Lelong H, Delalande C | title = Estrogen, a female hormone involved in spermatogenesis | journal = Adv Med Sci | volume = 57 | issue = 1 | pages = 31–6 | year = 2012 | pmid = 22440937 | doi = 10.2478/v10039-012-0005-y }}</ref><ref name="pmid24474947">{{cite journal | vauthors = Chimento A, Sirianni R, Casaburi I, Pezzi V | title = Role of estrogen receptors and g protein-coupled estrogen receptor in regulation of hypothalamus-pituitary-testis axis and spermatogenesis | journal = Front Endocrinol (Lausanne) | volume = 5 | pages = 1 | year = 2014 | pmid = 24474947 | pmc = 3893621 | doi = 10.3389/fendo.2014.00001 | doi-access = free }}</ref> GPER has been found to modulate [[gonadotropin-releasing hormone]] (GnRH) secretion in the [[hypothalamic-pituitary-gonadal axis|hypothalamic-pituitary-gonadal]] (HPG) [[hypothalamic-pituitary-gonadal axis|axis]].<ref name="pmid24474947" />


=== Cardiovascular effects ===
=== Cardiovascular effects ===
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== Role in cancer ==
== Role in cancer ==
Although GPER signaling was originally thought to be tumor-promoting in breast cancer,<ref name="LappanoPisano2014">{{cite journal | vauthors = Lappano R, Pisano A, Maggiolini M | title = GPER Function in Breast Cancer: An Overview | journal = Frontiers in Endocrinology | volume = 5 | pages = 66 | year = 2014 | pmid = 24834064 | doi = 10.3389/fendo.2014.00066 | pmc = 4018520 }}</ref> subsequent reports suggest that nonclassical estrogen signaling is tumor suppressive in breast cancer.<ref name="WeiChen2014">{{cite journal | vauthors = Wei W, Chen ZJ, Zhang KS, Yang XL, Wu YM, Chen XH, Huang HB, Liu HL, Cai SH, Du J, Wang HS | display-authors = 6 | title = The activation of G protein-coupled receptor 30 (GPR30) inhibits proliferation of estrogen receptor-negative breast cancer cells in vitro and in vivo | journal = Cell Death & Disease | volume = 5 | issue = 10 | pages = e1428 | date = October 2014 | pmid = 25275589 | doi = 10.1038/cddis.2014.398 | pmc = 4649509 }}</ref><ref name="WeißenbornIgnatov2014">{{cite journal | vauthors = Weißenborn C, Ignatov T, Ochel HJ, Costa SD, Zenclussen AC, Ignatova Z, Ignatov A | title = GPER functions as a tumor suppressor in triple-negative breast cancer cells | journal = Journal of Cancer Research and Clinical Oncology | volume = 140 | issue = 5 | pages = 713–23 | date = May 2014 | pmid = 24553912 | doi = 10.1007/s00432-014-1620-8 | s2cid = 9727742 }}</ref><ref name="WeißenbornIgnatov2014b">{{cite journal | vauthors = Weißenborn C, Ignatov T, Poehlmann A, Wege AK, Costa SD, Zenclussen AC, Ignatov A | title = GPER functions as a tumor suppressor in MCF-7 and SK-BR-3 breast cancer cells | journal = Journal of Cancer Research and Clinical Oncology | volume = 140 | issue = 4 | pages = 663–71 | date = April 2014 | pmid = 24515910 | doi = 10.1007/s00432-014-1598-2 | s2cid = 23338841 }}</ref> 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.{{Citation needed|date=December 2019|reason=removed citation to predatory publisher content}} In line with findings in breast cancer, GPER signaling has also been shown to be tumor suppressive in adrenocortical carcinoma,<ref name="Chimento2015">{{cite journal | vauthors = Chimento A, Sirianni R, Casaburi I, Zolea F, Rizza P, Avena P, Malivindi R, De Luca A, Campana C, Martire E, Domanico F, Fallo F, Carpinelli G, Cerquetti L, Amendola D, Stigliano A, Pezz V | display-authors = 6 | title = GPER agonist G-1 decreases adrenocortical carcinoma (ACC) cell growth in vitro and in vivo | journal = Oncotarget | volume = 6 | issue = 22 | pages = 13 | date = 7 Aug 2015 | pmid = 26131713 | doi = 10.18632/oncotarget.4241 | pmc = 4662484 | doi-access = free }}</ref> colorectal cancer,<ref name="LiuChen2017">{{cite journal | vauthors = Liu Q, Chen Z, Jiang G, Zhou Y, Yang X, Huang H, Liu H, Du J, Wang H | display-authors = 6 | title = Epigenetic down regulation of G protein-coupled estrogen receptor (GPER) functions as a tumor suppressor in colorectal cancer | journal = Molecular Cancer | volume = 16 | issue = 1 | pages = 87 | date = May 2017 | pmid = 28476123 | doi = 10.1186/s12943-017-0654-3 | pmc = 5418684 | doi-access = free }}</ref> endometrial cancer,<ref name="SkrzypczakSchüler2013">{{cite journal | vauthors = Skrzypczak M, Schüler S, Lattrich C, Ignatov A, Ortmann O, Treeck O | title = G protein-coupled estrogen receptor (GPER) expression in endometrial adenocarcinoma and effect of agonist G-1 on growth of endometrial adenocarcinoma cell lines | journal = Steroids | volume = 78 | issue = 11 | pages = 1087–91 | date = November 2013 | pmid = 23921077 | doi = 10.1016/j.steroids.2013.07.007 | s2cid = 25621881 }}</ref> Leydig cell tumors,<ref name="ChimentoCasaburi2013">{{cite journal | vauthors = Chimento A, Casaburi I, Bartucci M, Patrizii M, Dattilo R, Avena P, Andò S, Pezzi V, Sirianni R | display-authors = 6 | title = Selective GPER activation decreases proliferation and activates apoptosis in tumor Leydig cells | journal = Cell Death & Disease | volume = 4 | issue = 8 | pages = e747 | date = August 2013 | pmid = 23907461 | doi = 10.1038/cddis.2013.275 | pmc = 3763437 | doi-access = free }}</ref> non-small cell lung cancer,<ref name="ZhuHuang2016">{{cite journal | vauthors = Zhu G, Huang Y, Wu C, Wei D, Shi Y | title = Activation of G-Protein-Coupled Estrogen Receptor Inhibits the Migration of Human Nonsmall Cell Lung Cancer Cells via IKK-β/NF-κB Signals | journal = DNA and Cell Biology | volume = 35 | issue = 8 | pages = 434–42 | date = August 2016 | pmid = 27082459 | doi = 10.1089/dna.2016.3235 }}</ref> gastric cancer,<ref name="TianZhan2019">{{cite journal | vauthors = Tian S, Zhan N, Li R, Dong W | title = Downregulation of G Protein-Coupled Estrogen Receptor (GPER) is Associated with Reduced Prognosis in Patients with Gastric Cancer | journal = Medical Science Monitor | volume = 25 | pages = 3115–3126 | date = April 2019 | pmid = 31028714 | doi = 10.12659/MSM.913634 | pmc = 6503750 }}</ref> liver cancer,<ref name="WeiChen2016">{{cite journal | vauthors = Wei T, Chen W, Wen L, Zhang J, Zhang Q, Yang J, Liu H, Chen BW, Zhou Y, Feng X, Yang Q, Bai X, Liang T | display-authors = 6 | title = G protein-coupled estrogen receptor deficiency accelerates liver tumorigenesis by enhancing inflammation and fibrosis | journal = Cancer Letters | volume = 382 | issue = 2 | pages = 195–202 | date = November 2016 | pmid = 27594673 | doi = 10.1016/j.canlet.2016.08.012 }}</ref> melanoma,<ref name="RibeiroSantos2017">{{cite journal | vauthors = Ribeiro MP, Santos AE, Custódio JB | title = The activation of the G protein-coupled estrogen receptor (GPER) inhibits the proliferation of mouse melanoma K1735-M2 cells | journal = Chemico-Biological Interactions | volume = 277 | pages = 176–184 | date = November 2017 | pmid = 28947257 | doi = 10.1016/j.cbi.2017.09.017 }}</ref> osteosarcoma,<ref name="WangChen2018">{{cite journal | vauthors = Wang Z, Chen X, Zhao Y, Jin Y, Zheng J | title = G-protein-coupled estrogen receptor suppresses the migration of osteosarcoma cells via post-translational regulation of Snail | journal = Journal of Cancer Research and Clinical Oncology | volume = 145 | issue = 1 | pages = 87–96 | date = January 2019 | pmid = 30341688 | doi = 10.1007/s00432-018-2768-4 | s2cid = 53010634 }}</ref> ovarian cancer,<ref name="IgnatovModl2013">{{cite journal | vauthors = Ignatov T, Modl S, Thulig M, Weißenborn C, Treeck O, Ortmann O, Zenclussen A, Costa SD, Kalinski T, Ignatov A | display-authors = 6 | title = GPER-1 acts as a tumor suppressor in ovarian cancer | journal = Journal of Ovarian Research | volume = 6 | issue = 1 | pages = 51 | date = July 2013 | pmid = 23849542 | doi = 10.1186/1757-2215-6-51 | pmc = 3723961 | doi-access = free }}</ref> and prostate cancer.<ref name="LamOuyang2014">{{cite journal | vauthors = Lam HM, Ouyang B, Chen J, Ying J, Wang J, Wu CL, Jia L, Medvedovic M, Vessella RL, Ho SM | display-authors = 6 | title = Targeting GPR30 with G-1: a new therapeutic target for castration-resistant prostate cancer | journal = Endocrine-Related Cancer | volume = 21 | issue = 6 | pages = 903–14 | year = 2014 | pmid = 25287069 | doi = 10.1530/ERC-14-0402 | pmc = 4233119 | doi-access = free }}</ref> 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.
Although GPER signaling was originally thought to be tumor-promoting in breast cancer,<ref name="LappanoPisano2014">{{cite journal | vauthors = Lappano R, Pisano A, Maggiolini M | title = GPER Function in Breast Cancer: An Overview | journal = Frontiers in Endocrinology | volume = 5 | pages = 66 | year = 2014 | pmid = 24834064 | doi = 10.3389/fendo.2014.00066 | pmc = 4018520 | doi-access = free }}</ref> subsequent reports suggest that nonclassical estrogen signaling is tumor suppressive in breast cancer.<ref name="WeiChen2014">{{cite journal | vauthors = Wei W, Chen ZJ, Zhang KS, Yang XL, Wu YM, Chen XH, Huang HB, Liu HL, Cai SH, Du J, Wang HS | display-authors = 6 | title = The activation of G protein-coupled receptor 30 (GPR30) inhibits proliferation of estrogen receptor-negative breast cancer cells in vitro and in vivo | journal = Cell Death & Disease | volume = 5 | issue = 10 | pages = e1428 | date = October 2014 | pmid = 25275589 | doi = 10.1038/cddis.2014.398 | pmc = 4649509 }}</ref><ref name="WeißenbornIgnatov2014">{{cite journal | vauthors = Weißenborn C, Ignatov T, Ochel HJ, Costa SD, Zenclussen AC, Ignatova Z, Ignatov A | title = GPER functions as a tumor suppressor in triple-negative breast cancer cells | journal = Journal of Cancer Research and Clinical Oncology | volume = 140 | issue = 5 | pages = 713–23 | date = May 2014 | pmid = 24553912 | doi = 10.1007/s00432-014-1620-8 | s2cid = 9727742 }}</ref><ref name="WeißenbornIgnatov2014b">{{cite journal | vauthors = Weißenborn C, Ignatov T, Poehlmann A, Wege AK, Costa SD, Zenclussen AC, Ignatov A | title = GPER functions as a tumor suppressor in MCF-7 and SK-BR-3 breast cancer cells | journal = Journal of Cancer Research and Clinical Oncology | volume = 140 | issue = 4 | pages = 663–71 | date = April 2014 | pmid = 24515910 | doi = 10.1007/s00432-014-1598-2 | s2cid = 23338841 }}</ref> 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.{{Citation needed|date=December 2019|reason=removed citation to predatory publisher content}} In line with findings in breast cancer, GPER signaling has also been shown to be tumor suppressive in adrenocortical carcinoma,<ref name="Chimento2015">{{cite journal | vauthors = Chimento A, Sirianni R, Casaburi I, Zolea F, Rizza P, Avena P, Malivindi R, De Luca A, Campana C, Martire E, Domanico F, Fallo F, Carpinelli G, Cerquetti L, Amendola D, Stigliano A, Pezz V | display-authors = 6 | title = GPER agonist G-1 decreases adrenocortical carcinoma (ACC) cell growth in vitro and in vivo | journal = Oncotarget | volume = 6 | issue = 22 | pages = 19190–19203 | date = 7 Aug 2015 | pmid = 26131713 | doi = 10.18632/oncotarget.4241 | pmc = 4662484 | doi-access = free }}</ref> colorectal cancer,<ref name="LiuChen2017">{{cite journal | vauthors = Liu Q, Chen Z, Jiang G, Zhou Y, Yang X, Huang H, Liu H, Du J, Wang H | display-authors = 6 | title = Epigenetic down regulation of G protein-coupled estrogen receptor (GPER) functions as a tumor suppressor in colorectal cancer | journal = Molecular Cancer | volume = 16 | issue = 1 | pages = 87 | date = May 2017 | pmid = 28476123 | doi = 10.1186/s12943-017-0654-3 | pmc = 5418684 | doi-access = free }}</ref> endometrial cancer,<ref name="SkrzypczakSchüler2013">{{cite journal | vauthors = Skrzypczak M, Schüler S, Lattrich C, Ignatov A, Ortmann O, Treeck O | title = G protein-coupled estrogen receptor (GPER) expression in endometrial adenocarcinoma and effect of agonist G-1 on growth of endometrial adenocarcinoma cell lines | journal = Steroids | volume = 78 | issue = 11 | pages = 1087–91 | date = November 2013 | pmid = 23921077 | doi = 10.1016/j.steroids.2013.07.007 | s2cid = 25621881 }}</ref> Leydig cell tumors,<ref name="ChimentoCasaburi2013">{{cite journal | vauthors = Chimento A, Casaburi I, Bartucci M, Patrizii M, Dattilo R, Avena P, Andò S, Pezzi V, Sirianni R | display-authors = 6 | title = Selective GPER activation decreases proliferation and activates apoptosis in tumor Leydig cells | journal = Cell Death & Disease | volume = 4 | issue = 8 | pages = e747 | date = August 2013 | pmid = 23907461 | doi = 10.1038/cddis.2013.275 | pmc = 3763437 | doi-access = free }}</ref> non-small cell lung cancer,<ref name="ZhuHuang2016">{{cite journal | vauthors = Zhu G, Huang Y, Wu C, Wei D, Shi Y | title = Activation of G-Protein-Coupled Estrogen Receptor Inhibits the Migration of Human Nonsmall Cell Lung Cancer Cells via IKK-β/NF-κB Signals | journal = DNA and Cell Biology | volume = 35 | issue = 8 | pages = 434–42 | date = August 2016 | pmid = 27082459 | doi = 10.1089/dna.2016.3235 }}</ref> gastric cancer,<ref name="TianZhan2019">{{cite journal | vauthors = Tian S, Zhan N, Li R, Dong W | title = Downregulation of G Protein-Coupled Estrogen Receptor (GPER) is Associated with Reduced Prognosis in Patients with Gastric Cancer | journal = Medical Science Monitor | volume = 25 | pages = 3115–3126 | date = April 2019 | pmid = 31028714 | doi = 10.12659/MSM.913634 | pmc = 6503750 }}</ref> liver cancer,<ref name="WeiChen2016">{{cite journal | vauthors = Wei T, Chen W, Wen L, Zhang J, Zhang Q, Yang J, Liu H, Chen BW, Zhou Y, Feng X, Yang Q, Bai X, Liang T | display-authors = 6 | title = G protein-coupled estrogen receptor deficiency accelerates liver tumorigenesis by enhancing inflammation and fibrosis | journal = Cancer Letters | volume = 382 | issue = 2 | pages = 195–202 | date = November 2016 | pmid = 27594673 | doi = 10.1016/j.canlet.2016.08.012 }}</ref> melanoma,<ref name="RibeiroSantos2017">{{cite journal | vauthors = Ribeiro MP, Santos AE, Custódio JB | title = The activation of the G protein-coupled estrogen receptor (GPER) inhibits the proliferation of mouse melanoma K1735-M2 cells | journal = Chemico-Biological Interactions | volume = 277 | pages = 176–184 | date = November 2017 | pmid = 28947257 | doi = 10.1016/j.cbi.2017.09.017 }}</ref> osteosarcoma,<ref name="WangChen2018">{{cite journal | vauthors = Wang Z, Chen X, Zhao Y, Jin Y, Zheng J | title = G-protein-coupled estrogen receptor suppresses the migration of osteosarcoma cells via post-translational regulation of Snail | journal = Journal of Cancer Research and Clinical Oncology | volume = 145 | issue = 1 | pages = 87–96 | date = January 2019 | pmid = 30341688 | doi = 10.1007/s00432-018-2768-4 | s2cid = 53010634 }}</ref> ovarian cancer,<ref name="IgnatovModl2013">{{cite journal | vauthors = Ignatov T, Modl S, Thulig M, Weißenborn C, Treeck O, Ortmann O, Zenclussen A, Costa SD, Kalinski T, Ignatov A | display-authors = 6 | title = GPER-1 acts as a tumor suppressor in ovarian cancer | journal = Journal of Ovarian Research | volume = 6 | issue = 1 | pages = 51 | date = July 2013 | pmid = 23849542 | doi = 10.1186/1757-2215-6-51 | pmc = 3723961 | doi-access = free }}</ref> and prostate cancer.<ref name="LamOuyang2014">{{cite journal | vauthors = Lam HM, Ouyang B, Chen J, Ying J, Wang J, Wu CL, Jia L, Medvedovic M, Vessella RL, Ho SM | display-authors = 6 | title = Targeting GPR30 with G-1: a new therapeutic target for castration-resistant prostate cancer | journal = Endocrine-Related Cancer | volume = 21 | issue = 6 | pages = 903–14 | year = 2014 | pmid = 25287069 | doi = 10.1530/ERC-14-0402 | pmc = 4233119 | doi-access = free }}</ref> 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.


== Role in neurological disorders ==
== Role in neurological disorders ==
GPER is broadly expressed on the nervous system, and GPER activation promotes beneficial effects in several brain disorders.<ref>{{Cite journal|last1=Roque|first1=C.|last2=Mendes-Oliveira|first2=J.|last3=Duarte-Chendo|first3=C.|last4=Baltazar|first4=G.|date=October 2019|title=The role of G protein-coupled estrogen receptor 1 on neurological disorders|url=https://pubmed.ncbi.nlm.nih.gov/31513775/|journal=Frontiers in Neuroendocrinology|volume=55|pages=100786|doi=10.1016/j.yfrne.2019.100786|issn=1095-6808|pmid=31513775}}</ref> A study suggests that GPER levels were significantly lower in children with ADHD compared to controls.<ref>{{Cite journal|last1=Sahin|first1=Nilfer|last2=Altun|first2=Hatice|last3=Kurutaş|first3=Ergül Belge|last4=Fındıklı|first4=Ebru|date=2018-05-20|title=Evaluation of estrogen and G protein-coupled estrogen receptor 1 (GPER) levels in drug-naïve patients with attention deficit hyperactivity disorder (ADHD)|url=https://pubmed.ncbi.nlm.nih.gov/29659348/|journal=Bosnian Journal of Basic Medical Sciences|volume=18|issue=2|pages=126–131|doi=10.17305/bjbms.2018.2942|issn=1840-4812|pmc=5988531|pmid=29659348}}</ref>
GPER is broadly expressed on the nervous system, and GPER activation promotes beneficial effects in several brain disorders.<ref>{{Cite journal|last1=Roque|first1=C.|last2=Mendes-Oliveira|first2=J.|last3=Duarte-Chendo|first3=C.|last4=Baltazar|first4=G.|date=October 2019|title=The role of G protein-coupled estrogen receptor 1 on neurological disorders|url=https://pubmed.ncbi.nlm.nih.gov/31513775/|journal=Frontiers in Neuroendocrinology|volume=55|pages=100786|doi=10.1016/j.yfrne.2019.100786|issn=1095-6808|pmid=31513775|s2cid=202043731 }}</ref> A study suggests that GPER levels were significantly lower in children with ADHD compared to controls.<ref>{{Cite journal|last1=Sahin|first1=Nilfer|last2=Altun|first2=Hatice|last3=Kurutaş|first3=Ergül Belge|last4=Fındıklı|first4=Ebru|date=2018-05-20|title=Evaluation of estrogen and G protein-coupled estrogen receptor 1 (GPER) levels in drug-naïve patients with attention deficit hyperactivity disorder (ADHD)|journal=Bosnian Journal of Basic Medical Sciences|volume=18|issue=2|pages=126–131|doi=10.17305/bjbms.2018.2942|issn=1840-4812|pmc=5988531|pmid=29659348}}</ref>


==See also==
==See also==

Revision as of 00:34, 10 June 2022

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 IDsOMIM: 601805; MGI: 1924104; HomoloGene: 15855; GeneCards: GPER1; OMA:GPER1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

2852

76854

Ensembl

ENSG00000164850

ENSMUSG00000053647

UniProt

Q99527

Q8BMP4

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: 139.41 – 139.41 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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]

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]

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.[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]

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.[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]

Animal studies

Reproductive tissue

Estradiol produces cell proliferation in both normal and malignant breast epithelial tissue.[23][24] However, GPER knockout mice show no overt mammary phenotype, unlike ERα knockout mice, but similarly to ERβ knockout mice.[23] 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.[23] GPER is expressed in germ cells and has been found to be essential for male fertility, specifically, in spermatogenesis.[25][26][27][28] GPER has been found to modulate gonadotropin-releasing hormone (GnRH) secretion in the hypothalamic-pituitary-gonadal (HPG) axis.[28]

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.[29] GPER also regulates components of the renin–angiotensin system, which also controls blood pressure,[30][31] and is required for superoxide-mediated cardiovascular function and aging.[32]

Central nervous system activity

GPER and ERα, but not ERβ, have been found to mediate the antidepressant-like effects of estradiol.[33][34][35] Contrarily, activation of GPER has been found to be anxiogenic in mice, while activation of ERβ has been found to be anxiolytic.[36] 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.[35][37] It is speculated that activation of GPER may be the mechanism by which estradiol mediates rapid effects on the oxytocin system,[35][37] for instance, rapidly increasing oxytocin receptor expression.[38] 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.[38] 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.[39][40]

Metabolic roles

Female GPER knockout mice display hyperglycemia and impaired glucose tolerance, reduced body growth, and increased blood pressure.[41] 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.[42][43] The GPER-selective agonist G-1 shows therapeutic efficacy in mouse models of obesity and diabetes.[44]

Role in cancer

Although GPER signaling was originally thought to be tumor-promoting in breast cancer,[45] subsequent reports suggest that nonclassical estrogen signaling is tumor suppressive in breast cancer.[46][47][48] 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.[citation needed] In line with findings in breast cancer, GPER signaling has also been shown to be tumor suppressive in adrenocortical carcinoma,[49] colorectal cancer,[50] endometrial cancer,[51] Leydig cell tumors,[52] non-small cell lung cancer,[53] gastric cancer,[54] liver cancer,[55] melanoma,[56] osteosarcoma,[57] ovarian cancer,[58] and prostate cancer.[59] 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.

Role in neurological disorders

GPER is broadly expressed on the nervous system, and GPER activation promotes beneficial effects in several brain disorders.[60] A study suggests that GPER levels were significantly lower in children with ADHD compared to controls.[61]

See also

References

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