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词条 GPER
释义

  1. Discovery

  2. Ligands

  3. Function

  4. Animal studies

      Reproductive tissue    Cardiovascular effects    Central nervous system activity    Metabolic roles  

  5. Clinical significance

  6. See also

  7. References

  8. External links

{{Infobox gene}}

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.

Discovery

The classical estrogen receptors first characterized in 1958[2] 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.[3] 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.[3]

Ligands

GPER binds estradiol though not other endogenous estrogens, such as estrone or estriol, nor for other endogenous steroids, including progesterone, testosterone, and cortisol.[4][5][6][7] Although potentially involved in signaling by aldosterone, GPER does not show any detectable binding towards aldosterone.[8][9] Niacin and nicotinamide bind to the receptor in vitro with very low affinity.[10][11] CCL18 has been identified as an endogenous antagonist of the GPER.[12]

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.[4] This protein therefore plays a role in the rapid nongenomic signaling events widely observed following stimulation of cells and tissues with estradiol.[13] 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.[14]

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.[15][18] However, GPER knockout mice show no overt mammary phenotype, unlike ERα knockout mice, but similarly to ERβ knockout mice.[15] 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.[15] GPER is expressed in germ cells and has been found to be essential for male fertility, specifically, in spermatogenesis.[16][17][18][19] GPER has been found to modulate gonadotropin-releasing hormone (GnRH) secretion in the hypothalamic-pituitary-gonadal (HPG) axis.[19]

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.[20] GPER also regulates components of the renin–angiotensin system, which also controls blood pressure,[21][22] and is required for superoxide-mediated cardiovascular function and aging.[23]

Central nervous system activity

GPER and ERα, but not ERβ, have been found to mediate the antidepressant-like effects of estradiol.[24][25][26] Contrarily, activation of GPER has been found to be anxiogenic in mice, while activation of ERβ has been found to be anxiolytic.[27] 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.[26][28] It is speculated that activation of GPER may be the mechanism by which estradiol mediates rapid effects on the oxytocin system,[26][28] for instance, rapidly increasing oxytocin receptor expression.[29] 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.[29] 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.[30][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, 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.[33][34]

Clinical significance

GPER plays a role in breast cancer progression and tamoxifen resistance.[35] GPER has also been proposed as a biomarker in triple-negative breast cancer.[35] In patients with endometrial cancer GPER it is overexpressed and its associated with poor survival.[36] In other tumors, there is still a controversy over the role of GPER. For example in ovarian cancer, some studies indicate a link between GPER expression and poor prognosis, while other studies do not.[36]

See also

  • Membrane estrogen receptor
  • Gq-mER
  • ER-X
  • ERx

References

1. ^{{cite journal | vauthors = O'Dowd BF, Nguyen T, Marchese A, Cheng R, Lynch KR, Heng HH, Kolakowski LF, George SR | title = Discovery of three novel G-protein-coupled receptor genes | journal = Genomics | volume = 47 | issue = 2 | pages = 310–3 | date = Jan 1998 | pmid = 9479505 | doi = 10.1006/geno.1998.5095 }}
2. ^{{cite journal | vauthors = Jensen E | title = A conversation with Elwood Jensen. Interview by David D. Moore | journal = Annual Review of Physiology | volume = 74 | issue = | pages = 1–11 | year = 2012 | pmid = 21888507 | doi = 10.1146/annurev-physiol-020911-153327 }}
3. ^1 {{cite journal | vauthors = Vrtačnik P, Ostanek B, Mencej-Bedrač S, Marc J | title = The many faces of estrogen signaling | journal = Biochemia Medica | volume = 24 | issue = 3 | pages = 329–42 | year = 2014 | pmid = 25351351 | pmc = 4210253 | doi = 10.11613/BM.2014.035 }}
4. ^1 {{cite journal | vauthors = Revankar CM, Cimino DF, Sklar LA, Arterburn JB, Prossnitz ER | title = A transmembrane intracellular estrogen receptor mediates rapid cell signaling | journal = Science | volume = 307 | issue = 5715 | pages = 1625–30 | date = March 2005 | pmid = 15705806 | doi = 10.1126/science.1106943 }}
5. ^{{cite journal | vauthors = Filardo EJ, Thomas P | title = GPR30: a seven-transmembrane-spanning estrogen receptor that triggers EGF release | journal = Trends in Endocrinology and Metabolism | volume = 16 | issue = 8 | pages = 362–7 | date = October 2005 | pmid = 16125968 | doi = 10.1016/j.tem.2005.08.005 }}
6. ^{{cite journal | vauthors = Manavathi B, Kumar R | title = Steering estrogen signals from the plasma membrane to the nucleus: two sides of the coin | journal = Journal of Cellular Physiology | volume = 207 | issue = 3 | pages = 594–604 | date = June 2006 | pmid = 16270355 | doi = 10.1002/jcp.20551 }}
7. ^{{cite journal | vauthors = Prossnitz ER, Arterburn JB, Sklar LA | title = GPR30: A G protein-coupled receptor for estrogen | journal = Molecular and Cellular Endocrinology | volume = 265-266 | issue = | pages = 138–42 | date = February 2007 | pmid = 17222505 | pmc = 1847610 | doi = 10.1016/j.mce.2006.12.010 }}
8. ^{{cite journal | vauthors = Wendler A, Albrecht C, Wehling M | title = Nongenomic actions of aldosterone and progesterone revisited | journal = Steroids | volume = 77 | issue = 10 | pages = 1002–6 | date = August 2012 | pmid = 22285849 | doi = 10.1016/j.steroids.2011.12.023 }}
9. ^{{cite journal | vauthors = Cheng SB, Dong J, Pang Y, LaRocca J, Hixon M, Thomas P, Filardo EJ | title = 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 | journal = Molecular and Cellular Endocrinology | volume = 382 | issue = 2 | pages = 950–9 | date = February 2014 | pmid = 24239983 | doi = 10.1016/j.mce.2013.11.005 }}
10. ^{{cite journal | vauthors = Santolla MF, De Francesco EM, Lappano R, Rosano C, Abonante S, Maggiolini M | title = Niacin activates the G protein estrogen receptor (GPER)-mediated signalling | journal = Cell. Signal. | volume = 26 | issue = 7 | pages = 1466–1475 | date = July 2014 | pmid = 24662263 | doi = 10.1016/j.cellsig.2014.03.011 | quote = 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)}}
11. ^{{cite journal | vauthors = Barton M | title = Not lost in translation: Emerging clinical importance of the G protein-coupled estrogen receptor GPER | journal = Steroids | volume = 111| issue = | pages = 37–45| date = February 2016 | pmid = 26921679 | doi = 10.1016/j.steroids.2016.02.016 | quote = }}
12. ^{{cite journal |vauthors=Catusse J, Wollner S, Leick M, Schröttner P, Schraufstätter I, Burger M | title = Attenuation of CXCR4 responses by CCL18 in acute lymphocytic leukemia B cells | journal = J. Cell. Physiol. | volume = 225 | issue = 3 | pages = 792–800 |date=November 2010 | pmid = 20568229 | doi = 10.1002/jcp.22284 }}
13. ^{{cite web | title = Entrez Gene: GPR30 G protein-coupled receptor 30| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2852| accessdate = }}
14. ^{{cite journal | vauthors = Hazell GG, Yao ST, Roper JA, Prossnitz ER, O'Carroll AM, Lolait SJ | title = Localisation of GPR30, a novel G protein-coupled oestrogen receptor, suggests multiple functions in rodent brain and peripheral tissues | journal = The Journal of Endocrinology | volume = 202 | issue = 2 | pages = 223–36 | date = August 2009 | pmid = 19420011 | pmc = 2710976 | doi = 10.1677/JOE-09-0066 }}
15. ^1 2 {{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 }}
16. ^{{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 }}
17. ^{{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 }}
18. ^{{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 }}
19. ^1 {{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 | issue = | pages = 1 | year = 2014 | pmid = 24474947 | pmc = 3893621 | doi = 10.3389/fendo.2014.00001 }}
20. ^{{cite journal | vauthors = Meyer MR, Amann K, Field AS, Hu C, Hathaway HJ, Kanagy NL, Walker MK, Barton M, Prossnitz ER | title = Deletion of G protein-coupled estrogen receptor increases endothelial vasoconstriction | journal = Hypertension | volume = 59 | issue = 2 | pages = 507–12 | date = February 2012 | pmid = 22203741 | pmc = 3266468 | doi = 10.1161/HYPERTENSIONAHA.111.184606 | quote = The development of the GPER-selective agonist G-114 has facilitated studies that demonstrate GPER activation induces acute vasodilation and lowers blood pressure in rodents. We18 and others17,19 have shown that acute GPER-mediated vasodilator effects are at least partly endothelium- and NO-dependent.}}
21. ^{{cite journal | vauthors = Lindsey SH, Chappell MC | title = Evidence that the G protein-coupled membrane receptor GPR30 contributes to the cardiovascular actions of estrogen | journal = Gender Medicine | volume = 8 | issue = 6 | pages = 343–54 | date = December 2011 | pmid = 22153880 | pmc = 3240864 | doi = 10.1016/j.genm.2011.10.004 }}
22. ^{{cite journal | vauthors = Han G, Li F, Yu X, White RE | title = GPER: a novel target for non-genomic estrogen action in the cardiovascular system | journal = Pharmacological Research | volume = 71 | issue = | pages = 53–60 | date = May 2013 | pmid = 23466742 | doi = 10.1016/j.phrs.2013.02.008 }}
23. ^{{cite journal | vauthors = Meyer MR, Fredette NC, Daniel C, Sharma G, Amann K, Arterburn JB, Barton M, Prossnitz ER | title = Obligatory role for GPER in cardiovascular aging and disease | journal = Science Signaling | volume = 9 | issue = 452 | pages = ra105 | date = November 2016 | pmid = 27803283 | pmc = 5124501 | doi = 10.1126/scisignal.aag0240 }}
24. ^{{cite journal | vauthors = Estrada-Camarena E, López-Rubalcava C, Vega-Rivera N, Récamier-Carballo S, Fernández-Guasti A | title = Antidepressant effects of estrogens: a basic approximation | journal = Behav Pharmacol | volume = 21 | issue = 5–6 | pages = 451–64 | year = 2010 | pmid = 20700047 | doi = 10.1097/FBP.0b013e32833db7e9 }}
25. ^{{cite journal | vauthors = 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 | title = In vivo effects of a GPR30 antagonist | journal = Nat. Chem. Biol. | volume = 5 | issue = 6 | pages = 421–7 | year = 2009 | pmid = 19430488 | pmc = 2864230 | doi = 10.1038/nchembio.168 }}
26. ^1 2 {{cite journal | vauthors = Xu H, Qin S, Carrasco GA, Dai Y, Filardo EJ, Prossnitz ER, Battaglia G, Doncarlos LL, Muma NA | title = Extra-nuclear estrogen receptor GPR30 regulates serotonin function in rat hypothalamus | journal = Neuroscience | volume = 158 | issue = 4 | pages = 1599–607 | year = 2009 | pmid = 19095043 | pmc = 2747636 | doi = 10.1016/j.neuroscience.2008.11.028 }}
27. ^{{cite journal | vauthors = Kastenberger I, Lutsch C, Schwarzer C | title = Activation of the G-protein-coupled receptor GPR30 induces anxiogenic effects in mice, similar to oestradiol | journal = Psychopharmacology | volume = 221 | issue = 3 | pages = 527–35 | year = 2012 | pmid = 22143579 | pmc = 3350630 | doi = 10.1007/s00213-011-2599-3 }}
28. ^1 {{cite book |first = Elena | last =Choleris | name-list-format = vanc | title = Oxytocin, Vasopressin and Related Peptides in the Regulation of Behavior | url = https://books.google.com/books?id=8ZasDMxSI0UC&pg=PA10 | date=11 April 2013 | publisher = Cambridge University Press | isbn = 978-0-521-19035-0 | pages = 10– }}
29. ^1 {{cite book | first = Jeffrey D. | last = Blaustein | name-list-format = vanc | title = Handbook of Neurochemistry and Molecular Neurobiology: Behavioral Neurochemistry, Neuroendocrinology and Molecular Neurobiology | url = https://books.google.com/books?id=ez6A_UUDHVkC&pg=PA165 | date = 8 December 2006 | publisher = Springer Science & Business Media | isbn = 978-0-387-30362-8 | pages = 165– }}
30. ^{{cite journal | vauthors = Long N, Serey C, Sinchak K | title = 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 | journal = Hormones and Behavior | volume = 66 | issue = 4 | pages = 663–6 | date = September 2014 | pmid = 25245158 | doi = 10.1016/j.yhbeh.2014.09.008 | pmc=4254307}}
31. ^{{Cite journal|last=Long|first=Nathan|last2=Long|first2=Bertha|last3=Mana|first3=Asma|last4=Le|first4=Dream|last5=Nguyen|first5=Lam|last6=Chokr|first6=Sima|last7=Sinchak|first7=Kevin|date=2017-03-01|title=Tamoxifen and ICI 182,780 activate hypothalamic G protein-coupled estrogen receptor 1 to rapidly facilitate lordosis in female rats|journal=Hormones and Behavior|volume=89|pages=98–103|doi=10.1016/j.yhbeh.2016.12.013|pmc=5359066|pmid=28063803}}
32. ^{{cite journal |vauthors=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 | display-authors = 6 | title = 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 | journal = Endocrinology | volume = 150| issue = 2| pages = 687–98| year = 2008 | pmid = 18845638 | doi = 10.1210/en.2008-0623 }}
33. ^{{cite journal |vauthors=Ford J, Hajibeigi A, Long M, Hahner L, Gore C, Hsieh JT, Clegg D, Zerwekh J, Oz OK | title = GPR30 deficiency causes increased bone mass, mineralization, and growth plate proliferative activity in male mice | journal = J Bone Miner Res | volume = 26| issue = 2| pages = 298–307|date=August 2010 | pmid = 20734455 | doi = 10.1002/jbmr.209 | pmc = 3179349}}
34. ^{{cite journal | vauthors = Sharma G, Hu C, Brigman JL, Zhu G, Hathaway HJ, Prossnitz ER | title = GPER deficiency in male mice results in insulin resistance, dyslipidemia, and a proinflammatory state | journal = Endocrinology | volume = 154 | issue = 11 | pages = 4136–45 | date = November 2013 | pmid = 23970785 | pmc = 3800768 | doi = 10.1210/en.2013-1357 }}
35. ^1 2 {{cite journal | vauthors = Lappano R, Pisano A, Maggiolini M | title = GPER Function in Breast Cancer: An Overview | journal = Frontiers in Endocrinology | volume = 5 | issue = | pages = 66 | year = 2014 | pmid = 24834064 | pmc = 4018520 | doi = 10.3389/fendo.2014.00066 | department = review }}
36. ^1 {{cite journal | vauthors = Filardo EJ | title = A role for G-protein coupled estrogen receptor (GPER) in estrogen-induced carcinogenesis: Dysregulated glandular homeostasis, survival and metastasis | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 176 | issue = | pages = 38–48 | date = February 2018 | pmid = 28595943 | doi = 10.1016/j.jsbmb.2017.05.005 | department = review }}

External links

  • {{cite web | url = http://www.iuphar-db.org/GPCR/ChapterMenuForward?chapterID=1360 | title = Estrogen (G protein coupled) Receptor | accessdate = | format = | work = IUPHAR Database of Receptors and Ion Channels | publisher = International Union of Basic and Clinical Pharmacology | pages = | language = | archiveurl = | archivedate = | quote = }}
  • {{MeshName|GPER+protein}}
{{NLM content}}{{G protein-coupled receptors}}{{Estrogenics}}{{Use dmy dates|date=April 2017}}

1 : G protein-coupled receptors
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