GPER

GPER1
Identifiers
Aliases GPER1, Gper1, 6330420K13Rik, CMKRL2, Ceprl, FEG-1, GPCR-Br, Gper, Gpr30, CEPR, DRY12, LERGU, LERGU2, LyGPR, mER, G protein-coupled estrogen receptor 1
External IDs MGI: 1924104 HomoloGene: 15855 GeneCards: GPER1
Targeted by Drug
17β-estradiol, tamoxifen[1]
RNA expression pattern


More reference expression data
Orthologs
Species Human Mouse
Entrez

2852

76854

Ensembl

ENSG00000164850

ENSMUSG00000053647

UniProt

Q99527

Q8BMP4

RefSeq (mRNA)

NM_001031682
NM_001039966
NM_001098201
NM_001505

NM_029771

RefSeq (protein)

NP_001035055.1
NP_001091671.1
NP_001496.1

NP_084047.2

Location (UCSC) Chr 7: 1.08 – 1.09 Mb Chr 5: 139.42 – 139.43 Mb
PubMed search [2] [3]
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.[4] 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.

Discovery

The classical estrogen receptors first characterized in 1958[5] 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.[6] In 2005, it was discovered that a member of the G protein-coupled receptor (GPCR) family, GPR30 also binds with high affinity of estradiol and is responsible in part for the rapid non-genomic actions of estradiol. Based on its ability to be bind estradiol, GPR30 was renamed as G protein-coupled estrogen receptor (GPER). Unlike other members of the GPCR family, which reside in the outer membrane of cells, GPER is localized to the endoplasmic reticulum.[6]

Ligands

GPER binds estradiol though not other endogenous estrogens, such as estrone or estriol, nor for other endogenous steroids, including progesterone, testosterone, and cortisol.[7][8][9][10] However, GPER does show high affinity for aldosterone.[11] Niacin and nicotinamide bind to the receptor in vitro.[12][13]

CCL18 has been identified as an endogenous antagonist of the GPER.[14]

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 endoplasmic reticulum. The protein binds estradiol, resulting in intracellular calcium mobilization and synthesis of phosphatidylinositol (3,4,5)-trisphosphate in the nucleus. This protein therefore plays a role in the rapid nongenomic signaling events widely observed following stimulation of cells and tissues with estradiol.[15] 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.[16]

Animal studies

Reproductive tissue

GPER is expressed in the breasts, and activation by estradiol produces cell proliferation in both normal and malignant breast epithelial tissue.[17][18] However, GPER knockout mice show no overt mammary phenotype, unlike ERα knockout mice, but similarly to ERβ knockout mice.[17] 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.[17] GPER is expressed in germ cells and has been found to be essential for male fertility, specifically, in spermatogenesis.[19][20][21][22] GPER has been found to modulate gonadotropin-releasing hormone (GnRH) secretion in the hypothalamic-pituitary-gonadal (HPG) axis.[22]

Cardiovascular effects

GPER is expressed in the blood vessel endothelium and is responsible for vasodilation and as a result, blood pressure lowering effects of estrogen. GPER also regulates components of the renin–angiotensin system which also controls blood pressure.[23][24]

Central nervous system activity

GPER and ERα, but not ERβ, have been found to mediate the antidepressant-like effects of estradiol.[25][26][27] Contrarily, activation of GPER has been found to be anxiogenic in mice, while activation of ERβ has been found to be anxiolytic.[28] 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.[27][29] It is speculated that activation of GPER may be the mechanism by which estradiol mediates rapid effects on the oxytocin system,[27][29] for instance, rapidly increasing oxytocin receptor expression.[30] 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.[30]

Estradiol, as well as tamoxifen and fulvestrant, have been found to rapidly induce lordosis through activation of the GPER in female rats.[31]

Metabolic roles

Female GPER knockout mice display hyperglycemia and impaired glucose tolerance, reduced body growth, and increased blood pressure.[32] Male GPER knockout mice are observed to have increased growth, body fat, increased osteoblast function (mineralization) resulting in higher bone mineral density and trabecular bone volume, and persistent growth plate activity resulting in longer bones.[33]

Clinical significance

GPER plays a role in breast cancer progression and tamoxifen resistance.[34] GPER has also been proposed as a biomarker in triple-negative breast cancer.[34]

See also

References

  1. ↑ "Drugs that physically interact with G-protein coupled estrogen receptor 1 view/edit references on wikidata".
  2. ↑ "Human PubMed Reference:".
  3. ↑ "Mouse PubMed Reference:".
  4. ↑ O'Dowd BF, Nguyen T, Marchese A, Cheng R, Lynch KR, Heng HH, Kolakowski LF, George SR (Jan 1998). "Discovery of three novel G-protein-coupled receptor genes". Genomics. 47 (2): 310–3. doi:10.1006/geno.1998.5095. PMID 9479505.
  5. ↑ 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.
  6. 1 2 Vrtačnik P, Ostanek B, Mencej-Bedrač S, Marc J (2014). "The many faces of estrogen signaling". Biochemia Medica. 24 (3): 329–42. doi:10.11613/BM.2014.035. PMC 4210253Freely accessible. PMID 25351351.
  7. ↑ Revankar CM, Cimino DF, Sklar LA, Arterburn JB, Prossnitz ER (Mar 2005). "A transmembrane intracellular estrogen receptor mediates rapid cell signaling". Science. 307 (5715): 1625–30. doi:10.1126/science.1106943. PMID 15705806.
  8. ↑ Filardo EJ, Thomas P (Oct 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.
  9. ↑ Manavathi B, Kumar R (Jun 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.
  10. ↑ Prossnitz ER, Arterburn JB, Sklar LA (Feb 2007). "GPR30: A G protein-coupled receptor for estrogen". Molecular and Cellular Endocrinology. 265-266: 138–42. doi:10.1016/j.mce.2006.12.010. PMC 1847610Freely accessible. PMID 17222505.
  11. ↑ Wendler A, Albrecht C, Wehling M (Aug 2012). "Nongenomic actions of aldosterone and progesterone revisited". Steroids. 77 (10): 1002–6. doi:10.1016/j.steroids.2011.12.023. PMID 22285849.
  12. ↑ 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)
  13. ↑ Barton M (February 2016). "Not lost in translation: Emerging clinical importance of the G protein-coupled estrogen receptor GPER". Steroids. doi:10.1016/j.steroids.2016.02.016. PMID 26921679.
  14. ↑ 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. doi:10.1002/jcp.22284. PMID 20568229.
  15. ↑ "Entrez Gene: GPR30 G protein-coupled receptor 30".
  16. ↑ Hazell GG, Yao ST, Roper JA, Prossnitz ER, O'Carroll AM, Lolait SJ (Aug 2009). "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): 223–36. doi:10.1677/JOE-09-0066. PMC 2710976Freely accessible. PMID 19420011.
  17. 1 2 3 Scaling AL, Prossnitz ER, Hathaway HJ (2014). "GPER mediates estrogen-induced signaling and proliferation in human breast epithelial cells and normal and malignant breast". Horm Cancer. 5 (3): 146–60. doi:10.1007/s12672-014-0174-1. PMC 4091989Freely accessible. PMID 24718936.
  18. ↑ Lappano R, Pisano A, Maggiolini M (2014). "GPER Function in Breast Cancer: An Overview". Front Endocrinol (Lausanne). 5: 66. doi:10.3389/fendo.2014.00066. PMC 4018520Freely accessible. PMID 24834064.
  19. ↑ Carreau S, Bouraima-Lelong H, Delalande C (2011). "Estrogens: new players in spermatogenesis". Reprod Biol. 11 (3): 174–93. doi:10.1016/s1642-431x(12)60065-5. PMID 22139333.
  20. ↑ Carreau S, Bois C, Zanatta L, Silva FR, Bouraima-Lelong H, Delalande C (2011). "Estrogen signaling in testicular cells". Life Sci. 89 (15-16): 584–7. doi:10.1016/j.lfs.2011.06.004. PMID 21703280.
  21. ↑ Carreau S, Bouraima-Lelong H, Delalande C (2012). "Estrogen, a female hormone involved in spermatogenesis". Adv Med Sci. 57 (1): 31–6. doi:10.2478/v10039-012-0005-y. PMID 22440937.
  22. 1 2 Chimento A, Sirianni R, Casaburi I, Pezzi V (2014). "Role of estrogen receptors and g protein-coupled estrogen receptor in regulation of hypothalamus-pituitary-testis axis and spermatogenesis". Front Endocrinol (Lausanne). 5: 1. doi:10.3389/fendo.2014.00001. PMC 3893621Freely accessible. PMID 24474947.
  23. ↑ Lindsey SH, Chappell MC (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 3240864Freely accessible. PMID 22153880.
  24. ↑ Han G, Li F, Yu X, White RE (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. PMID 23466742.
  25. ↑ Estrada-Camarena E, López-Rubalcava C, Vega-Rivera N, Récamier-Carballo S, Fernández-Guasti A (2010). "Antidepressant effects of estrogens: a basic approximation". Behav Pharmacol. 21 (5-6): 451–64. doi:10.1097/FBP.0b013e32833db7e9. PMID 20700047.
  26. ↑ Dennis MK, Burai R, Ramesh C, Petrie WK, Alcon SN, Nayak TK, Bologa CG, Leitao A, Brailoiu E, Deliu E, Dun NJ, Sklar LA, Hathaway HJ, Arterburn JB, Oprea TI, Prossnitz ER (2009). "In vivo effects of a GPR30 antagonist". Nat. Chem. Biol. 5 (6): 421–7. doi:10.1038/nchembio.168. PMC 2864230Freely accessible. PMID 19430488.
  27. 1 2 3 Xu H, Qin S, Carrasco GA, Dai Y, Filardo EJ, Prossnitz ER, Battaglia G, Doncarlos LL, Muma NA (2009). "Extra-nuclear estrogen receptor GPR30 regulates serotonin function in rat hypothalamus". Neuroscience. 158 (4): 1599–607. doi:10.1016/j.neuroscience.2008.11.028. PMC 2747636Freely accessible. PMID 19095043.
  28. ↑ Kastenberger I, Lutsch C, Schwarzer C (2012). "Activation of the G-protein-coupled receptor GPR30 induces anxiogenic effects in mice, similar to oestradiol". Psychopharmacology (Berl.). 221 (3): 527–35. doi:10.1007/s00213-011-2599-3. PMC 3350630Freely accessible. PMID 22143579.
  29. 1 2 Choleris E (11 April 2013). Oxytocin, Vasopressin and Related Peptides in the Regulation of Behavior. Cambridge University Press. pp. 10–. ISBN 978-0-521-19035-0.
  30. 1 2 Blaustein JD (8 December 2006). Handbook of Neurochemistry and Molecular Neurobiology: Behavioral Neurochemistry, Neuroendocrinology and Molecular Neurobiology. Springer Science & Business Media. pp. 165–. ISBN 978-0-387-30362-8.
  31. ↑ Long N, Serey C, Sinchak K (September 2014). "17β-estradiol rapidly facilitates lordosis through G protein-coupled estrogen receptor 1 (GPER) via deactivation of medial preoptic nucleus μ-opioid receptors in estradiol primed female rats". Hormones and Behavior. 66 (4): 663–6. doi:10.1016/j.yhbeh.2014.09.008. PMC 4254307Freely accessible. PMID 25245158.
  32. ↑ Mårtensson UE, Salehi SA, Windahl S, Gomez MF, Swärd K, Daszkiewicz-Nilsson J, Wendt A, Andersson N, Hellstrand P, Grände PO, Owman C, Rosen CJ, Adamo ML, Lundquist I, Rorsman P, Nilsson BO, Ohlsson C, Olde B, Leeb-Lundberg LM (2008). "Deletion of the G protein-coupled Receptor GPR30 Impairs Glucose Tolerance, Reduces Bone Growth, Increases Blood Pressure, and Eliminates Estradiol-stimulated Insulin Release in Female Mice". Endocrinology. 150 (2): 687–98. doi:10.1210/en.2008-0623. PMID 18845638.
  33. ↑ Ford J, Hajibeigi A, Long M, Hahner L, Gore C, Hsieh JT, Clegg D, Zerwekh J, Oz OK (August 2010). "GPR30 deficiency causes increased bone mass, mineralization, and growth plate proliferative activity in male mice". J Bone Miner Res. 26 (2): 298–307. doi:10.1002/jbmr.209. PMID 20734455.
  34. 1 2 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 4018520Freely accessible. PMID 24834064.

Further reading

  • Filardo EJ (Feb 2002). "Epidermal growth factor receptor (EGFR) transactivation by estrogen via the G-protein-coupled receptor, GPR30: a novel signaling pathway with potential significance for breast cancer". The Journal of Steroid Biochemistry and Molecular Biology. 80 (2): 231–8. doi:10.1016/S0960-0760(01)00190-X. PMID 11897506. 
  • Filardo EJ, Thomas P (Oct 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. 
  • Bonaldo MF, Lennon G, Soares MB (Sep 1996). "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Research. 6 (9): 791–806. doi:10.1101/gr.6.9.791. PMID 8889548. 
  • Owman C, Blay P, Nilsson C, Lolait SJ (Nov 1996). "Cloning of human cDNA encoding a novel heptahelix receptor expressed in Burkitt's lymphoma and widely distributed in brain and peripheral tissues". Biochemical and Biophysical Research Communications. 228 (2): 285–92. doi:10.1006/bbrc.1996.1654. PMID 8920907. 
  • Feng Y, Gregor P (Feb 1997). "Cloning of a novel member of the G protein-coupled receptor family related to peptide receptors". Biochemical and Biophysical Research Communications. 231 (3): 651–4. doi:10.1006/bbrc.1997.6161. PMID 9070864. 
  • Kvingedal AM, Smeland EB (Apr 1997). "A novel putative G-protein-coupled receptor expressed in lung, heart and lymphoid tissue". FEBS Letters. 407 (1): 59–62. doi:10.1016/S0014-5793(97)00278-0. PMID 9141481. 
  • Carmeci C, Thompson DA, Ring HZ, Francke U, Weigel RJ (Nov 1997). "Identification of a gene (GPR30) with homology to the G-protein-coupled receptor superfamily associated with estrogen receptor expression in breast cancer". Genomics. 45 (3): 607–17. doi:10.1006/geno.1997.4972. PMID 9367686. 
  • Takada Y, Kato C, Kondo S, Korenaga R, Ando J (Nov 1997). "Cloning of cDNAs encoding G protein-coupled receptor expressed in human endothelial cells exposed to fluid shear stress". Biochemical and Biophysical Research Communications. 240 (3): 737–41. doi:10.1006/bbrc.1997.7734. PMID 9398636. 
  • Filardo EJ, Quinn JA, Bland KI, Frackelton AR (Oct 2000). "Estrogen-induced activation of Erk-1 and Erk-2 requires the G protein-coupled receptor homolog, GPR30, and occurs via trans-activation of the epidermal growth factor receptor through release of HB-EGF". Molecular Endocrinology. 14 (10): 1649–60. doi:10.1210/me.14.10.1649. PMID 11043579. 
  • Filardo EJ, Quinn JA, Frackelton AR, Bland KI (Jan 2002). "Estrogen action via the G protein-coupled receptor, GPR30: stimulation of adenylyl cyclase and cAMP-mediated attenuation of the epidermal growth factor receptor-to-MAPK signaling axis". Molecular Endocrinology. 16 (1): 70–84. doi:10.1210/me.16.1.70. PMID 11773440. 
  • Ahola TM, Purmonen S, Pennanen P, Zhuang YH, Tuohimaa P, Ylikomi T (May 2002). "Progestin upregulates G-protein-coupled receptor 30 in breast cancer cells". European Journal of Biochemistry / FEBS. 269 (10): 2485–90. doi:10.1046/j.1432-1033.2002.02912.x. PMID 12027886. 
  • Ahola TM, Manninen T, Alkio N, Ylikomi T (Sep 2002). "G protein-coupled receptor 30 is critical for a progestin-induced growth inhibition in MCF-7 breast cancer cells". Endocrinology. 143 (9): 3376–84. doi:10.1210/en.2001-211445. PMID 12193550. 
  • Ahola TM, Alkio N, Manninen T, Ylikomi T (Dec 2002). "Progestin and G protein-coupled receptor 30 inhibit mitogen-activated protein kinase activity in MCF-7 breast cancer cells". Endocrinology. 143 (12): 4620–6. doi:10.1210/en.2002-220492. PMID 12446589. 
  • Hamza A, Sarma MH, Sarma RH (Jun 2003). "Plausible interaction of an alpha-fetoprotein cyclopeptide with the G-protein-coupled receptor model GPR30: docking study by molecular dynamics simulated annealing". Journal of Biomolecular Structure & Dynamics. 20 (6): 751–8. doi:10.1080/07391102.2003.10506892. PMID 12744705. 
  • Kanda N, Watanabe S (Oct 2003). "17Beta-estradiol enhances the production of nerve growth factor in THP-1-derived macrophages or peripheral blood monocyte-derived macrophages". The Journal of Investigative Dermatology. 121 (4): 771–80. doi:10.1046/j.1523-1747.2003.12487.x. PMID 14632195. 
  • Kanda N, Watanabe S (Dec 2003). "17beta-estradiol inhibits oxidative stress-induced apoptosis in keratinocytes by promoting Bcl-2 expression". The Journal of Investigative Dermatology. 121 (6): 1500–9. doi:10.1111/j.1523-1747.2003.12617.x. PMID 14675202. 

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