GPER

Last updated
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 OMIM: 601805 MGI: 1924104 HomoloGene: 15855 GeneCards: GPER1
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 Mb Chr 5: 139.41 – 139.41 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/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]

Contents

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

Immunohistochemical and transcriptomic analyses of neoplasms derived from a variety of tissues including but not limited to: breast, [45] [46] [47] [48] [49] [50] endometrial, [51] ovarian, [52] and testicular [53] directly link GPER to advanced disease and prometastatic growth and survival. Experimental data also strong supports a pro-oncogenic role for GPER. First, GPER is required for the survival of tumor-initiating “stem” cells derived from patient-derived tumor xenografts (PDXs). [54] Secondly, less aggressive disease occurs upon the somatic cell silencing of GPER in a robust model of PyMT-induced breast carcinogenesis. [55] Additionally, GPER-selective ligands show efficacy in nonclinical and clinical settings. For example, the GPER antagonist, G36, delays the estrogen-dependent outgrowth of transplanted endometrial carcinoma in mice, [56] while the GPER agonist, G1, has been shown to attenuate the growth of patient-derived xenografts of pancreatic ductal adenocarcinoma. [57]

A contrary argument that GPER may be tumor suppressive has been hypothesized. [58] [59] However, it is important to note that Linnaeus Therapeutics is currently running NCI clinical trial (NCT04130516) using GPER agonist. LNS8801, as monotherapy or in the combination with the checkpoint inhibitor, pembroluzimab, for the treatment of multiple solid tumor malignancies.

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. [51]

See also

Related Research Articles

<span class="mw-page-title-main">Estrogen</span> Primary female sex hormones

Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal activity: estrone (E1), estradiol (E2), and estriol (E3). Estradiol, an estrane, is the most potent and prevalent. Another estrogen called estetrol (E4) is produced only during pregnancy.

<span class="mw-page-title-main">Estradiol</span> Chemical compound

Estradiol (E2), also spelled oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of the estrous and menstrual female reproductive cycles. Estradiol is responsible for the development of female secondary sexual characteristics such as the breasts, widening of the hips and a female-associated pattern of fat distribution. It is also important in the development and maintenance of female reproductive tissues such as the mammary glands, uterus and vagina during puberty, adulthood and pregnancy. It also has important effects in many other tissues including bone, fat, skin, liver, and the brain.

<span class="mw-page-title-main">Estriol</span> Chemical compound

Estriol (E3), also spelled oestriol, is a steroid, a weak estrogen, and a minor female sex hormone. It is one of three major endogenous estrogens, the others being estradiol and estrone. Levels of estriol in women who are not pregnant are almost undetectable. However, during pregnancy, estriol is synthesized in very high quantities by the placenta and is the most produced estrogen in the body by far, although circulating levels of estriol are similar to those of other estrogens due to a relatively high rate of metabolism and excretion. Relative to estradiol, both estriol and estrone have far weaker activity as estrogens.

Steroid hormone receptors are found in the nucleus, cytosol, and also on the plasma membrane of target cells. They are generally intracellular receptors and initiate signal transduction for steroid hormones which lead to changes in gene expression over a time period of hours to days. The best studied steroid hormone receptors are members of the nuclear receptor subfamily 3 (NR3) that include receptors for estrogen and 3-ketosteroids. In addition to nuclear receptors, several G protein-coupled receptors and ion channels act as cell surface receptors for certain steroid hormones.

<span class="mw-page-title-main">Selective estrogen receptor modulator</span> Drugs acting on the estrogen receptor

Selective estrogen receptor modulators (SERMs), also known as estrogen receptor agonist/antagonists (ERAAs), are a class of drugs that act on the estrogen receptor (ER). A characteristic that distinguishes these substances from pure ER agonists and antagonists is that their action is different in various tissues, thereby granting the possibility to selectively inhibit or stimulate estrogen-like action in various tissues.

Fulvestrant, sold under the brand name Faslodex among others, is a medication used to treat hormone receptor (HR)-positive metastatic breast cancer in postmenopausal women with disease progression as well as HR-positive, HER2-negative advanced breast cancer in combination with abemaciclib or palbociclib in women with disease progression after endocrine therapy. It is given by injection into a muscle.

<span class="mw-page-title-main">2-Methoxyestradiol</span> Chemical compound

2-Methoxyestradiol is a natural metabolite of estradiol and 2-hydroxyestradiol (2-OHE2). It is specifically the 2-methyl ether of 2-hydroxyestradiol. 2-Methoxyestradiol prevents the formation of new blood vessels that tumors need in order to grow (angiogenesis), hence it is an angiogenesis inhibitor. It also acts as a vasodilator and induces apoptosis in some cancer cell lines. 2-Methoxyestradiol is derived from estradiol, although it interacts poorly with the estrogen receptors. However, it retains activity as a high-affinity agonist of the G protein-coupled estrogen receptor (GPER).

<span class="mw-page-title-main">Estrogen receptor</span> Proteins activated by the hormone estrogen

Estrogen receptors (ERs) are a group of proteins found inside cells. They are receptors that are activated by the hormone estrogen (17β-estradiol). Two classes of ER exist: nuclear estrogen receptors, which are members of the nuclear receptor family of intracellular receptors, and membrane estrogen receptors (mERs), which are mostly G protein-coupled receptors. This article refers to the former (ER).

<span class="mw-page-title-main">Estrogen receptor alpha</span> Protein-coding gene in the species Homo sapiens

Estrogen receptor alpha (ERα), also known as NR3A1, is one of two main types of estrogen receptor, a nuclear receptor that is activated by the sex hormone estrogen. In humans, ERα is encoded by the gene ESR1.

<span class="mw-page-title-main">Estrogen receptor beta</span> Protein-coding gene in the species Homo sapiens

Estrogen receptor beta (ERβ) also known as NR3A2 is one of two main types of estrogen receptor—a nuclear receptor which is activated by the sex hormone estrogen. In humans ERβ is encoded by the ESR2 gene.

<span class="mw-page-title-main">Afimoxifene</span> Chemical compound

Afimoxifene, also known as 4-hydroxytamoxifen (4-OHT) and by its tentative brand name TamoGel, is a selective estrogen receptor modulator (SERM) of the triphenylethylene group and an active metabolite of tamoxifen. The drug is under development under the tentative brand name TamoGel as a topical gel for the treatment of hyperplasia of the breast. It has completed a phase II clinical trial for cyclical mastalgia, but further studies are required before afimoxifene can be approved for this indication and marketed.

Menerba, also known as Menopause Formula 101 (MF-101), is a botanical drug candidate that acts as a selective estrogen receptor modulator (SERM) which is being studied for its potential to relieve hot flashes associated with menopause. Menerba, an estrogen receptor beta (ERβ) agonist (ERBA), is part of a new class of receptor subtype-selective estrogens, which is selective in transcriptional regulation to one of the two known estrogen receptor (ER) subtypes. Menerba consists of 22 herbs that have been used historically in traditional Chinese medicine.

<span class="mw-page-title-main">Estrogen and neurodegenerative diseases</span>

Neurodegenerative diseases can disrupt the normal human homeostasis and result in abnormal estrogen levels. For example, neurodegenerative diseases can cause different physiological effects in males and females. In particular, estrogen studies have revealed complex interactions with neurodegenerative diseases. Estrogen was initially proposed to be a possible treatment for certain types of neurodegenerative diseases but a plethora of harmful side effects such as increased susceptibility to breast cancer and coronary heart disease overshadowed any beneficial outcomes. On the other hand, Estrogen Replacement Therapy has shown some positive effects with postmenopausal women. Estrogen and estrogen-like molecules form a large family of potentially beneficial alternatives that can have dramatic effects on human homeostasis and disease. Subsequently, large-scale efforts were initiated to screen for useful estrogen family molecules. Furthermore, scientists discovered new ways to synthesize estrogen-like compounds that can avoid many side effects.

Membrane estrogen receptors (mERs) are a group of receptors which bind estrogen. Unlike the estrogen receptor (ER), a nuclear receptor which mediates its effects via genomic mechanisms, mERs are cell surface receptors which rapidly alter cell signaling via modulation of intracellular signaling cascades. Putative mERs include membrane-associated ERα (mERα) and ERβ (mERβ), GPER (GPR30), GPRC6A, ER-X, ERx and Gq-mER.

<span class="mw-page-title-main">Propylpyrazoletriol</span> Chemical compound

Propylpyrazoletriol (PPT) is a synthetic, nonsteroidal agonist of ERα with 400-fold selectivity over ERβ that is used widely in scientific research to study the function of ERα. Though originally thought to be highly selective for ERα, PPT has subsequently been found to also act as an agonist of the GPER (GPR30).

The Gq-coupled membrane estrogen receptor (Gq-mER) is a G protein-coupled receptor present in the hypothalamus that has not yet been cloned. It is a membrane-associated receptor that is Gq-coupled to a phospholipase C–protein kinase C–protein kinase A (PLC–PKC–PKA) pathway. The receptor has been implicated in the control of energy homeostasis. Gq-mER is bound and activated by estradiol, and is a putative membrane estrogen receptor (mER). A nonsteroidal diphenylacrylamide derivative, STX, which is structurally related to 4-hydroxytamoxifen (afimoxifene), is an agonist of the receptor with greater potency than estradiol that has been discovered. Fulvestrant (ICI-182,780) has been identified as an antagonist of Gq-mER, but is not selective.

<span class="mw-page-title-main">2-Hydroxyestradiol</span> Chemical compound

2-Hydroxyestradiol (2-OHE2), also known as estra-1,3,5(10)-triene-2,3,17β-triol, is an endogenous steroid, catechol estrogen, and metabolite of estradiol, as well as a positional isomer of estriol.

E-SCREEN is a cell proliferation assay based on the enhanced proliferation of human breast cancer cells (MCF-7) in the presence of estrogen active substances. The E-SCREEN test is a tool to easily and rapidly assess estrogenic activity of suspected xenoestrogens. This bioassay measures estrogen-induced increase of the number of human breast cancer cell, which is biologically equivalent to the increase of mitotic activity in tissues of the genital tract. It was originally developed by Soto et al. and was included in the first version of the OECD Conceptual Framework for Testing and Assessment of Endocrine Disrupters published in 2012. However, due to failed validation, it was not included in the updated version of the framework published in 2018.

<span class="mw-page-title-main">7β-Hydroxyepiandrosterone</span> Chemical compound

7β-Hydroxyepiandrosterone (7β-OH-EPIA), also known as 5α-androstan-3β,7β-diol-17-one, is an endogenous androgen, estrogen, and neurosteroid that is produced from dehydroepiandrosterone and epiandrosterone. It has neuroprotective effects and, along with 7α-hydroxyepiandrosterone, may mediate the neuroprotective effects of DHEA. 7β-OH-EPIA may act as a highly potent antagonist of the G protein-coupled estrogen receptor (GPER).

Endocrine therapy is a common treatment for estrogen receptor positive breast cancer. However, resistance to this therapy can develop, leading to relapse and progression of disease. This highlights the need for new strategies to combat this resistance.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000164850 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000053647 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. O'Dowd BF, Nguyen T, Marchese A, Cheng R, Lynch KR, Heng HH, Kolakowski LF, George SR (January 1998). "Discovery of three novel G-protein-coupled receptor genes". Genomics. 47 (2): 310–3. doi:10.1006/geno.1998.5095. PMID   9479505.
  6. 1 2 3 4 Prossnitz ER, Arterburn JB (July 2015). "International Union of Basic and Clinical Pharmacology. XCVII. G Protein-Coupled Estrogen Receptor and Its Pharmacologic Modulators". Pharmacol. Rev. 67 (3): 505–40. doi:10.1124/pr.114.009712. PMC   4485017 . PMID   26023144.
  7. 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.
  8. 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   4210253 . PMID   25351351.
  9. 1 2 3 Revankar CM, Cimino DF, Sklar LA, Arterburn JB, Prossnitz ER (March 2005). "A transmembrane intracellular estrogen receptor mediates rapid cell signaling". Science. 307 (5715): 1625–30. Bibcode:2005Sci...307.1625R. doi: 10.1126/science.1106943 . PMID   15705806. S2CID   15789136.
  10. 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. S2CID   33801811.
  11. 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. S2CID   27712910.
  12. Prossnitz ER, Arterburn JB, Sklar LA (February 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   1847610 . PMID   17222505.
  13. 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. S2CID   28968323.
  14. 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. S2CID   28896943.
  15. 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)
  16. 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.
  17. 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. S2CID   24889239.
  18. Bologa CG, Revankar CM, Young SM, Edwards BS, Arterburn JB, Kiselyov AS, et al. (April 2006). "Virtual and biomolecular screening converge on a selective agonist for GPR30". Nature Chemical Biology. 2 (4): 207–12. doi:10.1038/nchembio775. PMID   16520733. S2CID   2364534.
  19. Dennis MK, Burai R, Ramesh C, Petrie WK, Alcon SN, Nayak TK, et al. (June 2009). "In vivo effects of a GPR30 antagonist". Nature Chemical Biology. 5 (6): 421–7. doi:10.1038/nchembio.168. PMC   2864230 . PMID   19430488.
  20. Dennis MK, Field AS, Burai R, Ramesh C, Petrie WK, Bologa CG, et al. (November 2011). "Identification of a GPER/GPR30 antagonist with improved estrogen receptor counterselectivity". The Journal of Steroid Biochemistry and Molecular Biology. 127 (3–5): 358–66. doi:10.1016/j.jsbmb.2011.07.002. PMC   3220788 . PMID   21782022.
  21. "Entrez Gene: GPR30 G protein-coupled receptor 30".
  22. Hazell GG, Yao ST, Roper JA, Prossnitz ER, O'Carroll AM, Lolait SJ (August 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   2710976 . PMID   19420011.
  23. 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   4091989 . PMID   24718936.
  24. Lappano R, Pisano A, Maggiolini M (2014). "GPER Function in Breast Cancer: An Overview". review. Frontiers in Endocrinology. 5: 66. doi: 10.3389/fendo.2014.00066 . PMC   4018520 . PMID   24834064.
  25. 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.
  26. 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.
  27. 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.
  28. 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   3893621 . PMID   24474947.
  29. Meyer MR, Amann K, Field AS, Hu C, Hathaway HJ, Kanagy NL, Walker MK, Barton M, Prossnitz ER (February 2012). "Deletion of G protein-coupled estrogen receptor increases endothelial vasoconstriction". Hypertension. 59 (2): 507–12. doi:10.1161/HYPERTENSIONAHA.111.184606. PMC   3266468 . PMID   22203741. 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.
  30. 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.
  31. Han G, Li F, Yu X, White RE (May 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.
  32. Meyer MR, Fredette NC, Daniel C, Sharma G, Amann K, Arterburn JB, Barton M, Prossnitz ER (November 2016). "Obligatory role for GPER in cardiovascular aging and disease". Science Signaling. 9 (452): ra105. doi:10.1126/scisignal.aag0240. PMC   5124501 . PMID   27803283.
  33. 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. S2CID   205595404.
  34. 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   2864230 . PMID   19430488.
  35. 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   2747636 . PMID   19095043.
  36. Kastenberger I, Lutsch C, Schwarzer C (2012). "Activation of the G-protein-coupled receptor GPR30 induces anxiogenic effects in mice, similar to oestradiol". Psychopharmacology. 221 (3): 527–35. doi:10.1007/s00213-011-2599-3. PMC   3350630 . PMID   22143579.
  37. 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.
  38. 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.
  39. 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   4254307 . PMID   25245158.
  40. Long N, Long B, Mana A, Le D, Nguyen L, Chokr S, Sinchak K (March 2017). "Tamoxifen and ICI 182,780 activate hypothalamic G protein-coupled estrogen receptor 1 to rapidly facilitate lordosis in female rats". Hormones and Behavior. 89: 98–103. doi:10.1016/j.yhbeh.2016.12.013. PMC   5359066 . PMID   28063803.
  41. Mårtensson UE, Salehi SA, Windahl S, Gomez MF, Swärd K, Daszkiewicz-Nilsson J, et al. (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.
  42. 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. PMC   3179349 . PMID   20734455.
  43. 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.
  44. Sharma G, Hu C, Staquicini DI, Brigman JL, Liu M, Mauvais-Jarvis F, et al. (January 2020). "Preclinical efficacy of the GPER-selective agonist G-1 in mouse models of obesity and diabetes". Science Translational Medicine. 12 (528): eaau5956. doi:10.1126/scitranslmed.aau5956. PMC   7083206 . PMID   31996464.
  45. Filardo, Edward J.; Graeber, Carl T.; Quinn, Jeffrey A.; Resnick, Murray B.; Giri, Dilip; DeLellis, Ronald A.; Steinhoff, Margaret M.; Sabo, Edmond (1 November 2006). "Distribution of GPR30, a seven membrane-spanning estrogen receptor, in primary breast cancer and its association with clinicopathologic determinants of tumor progression". Clinical Cancer Research: An Official Journal of the American Association for Cancer Research. 12 (21): 6359–6366. doi:10.1158/1078-0432.CCR-06-0860. ISSN   1078-0432. PMID   17085646.
  46. Arias-Pulido, Hugo; Royce, Melanie; Gong, Yun; Joste, Nancy; Lomo, Lesley; Lee, Sang-Joon; Chaher, Nabila; Verschraegen, Claire; Lara, Juanita; Prossnitz, Eric R.; Cristofanilli, Massimo (August 2010). "GPR30 and estrogen receptor expression: new insights into hormone dependence of inflammatory breast cancer". Breast Cancer Research and Treatment. 123 (1): 51–58. doi:10.1007/s10549-009-0631-7. ISSN   1573-7217. PMC   2904403 . PMID   19902352.
  47. Ignatov, Atanas; Ignatov, Tanja; Weissenborn, Christine; Eggemann, Holm; Bischoff, Joachim; Semczuk, Andrzej; Roessner, Albert; Costa, Serban Dan; Kalinski, Thomas (July 2011). "G-protein-coupled estrogen receptor GPR30 and tamoxifen resistance in breast cancer". Breast Cancer Research and Treatment. 128 (2): 457–466. doi:10.1007/s10549-011-1584-1. ISSN   1573-7217. PMID   21607586.
  48. Sjöström, Martin; Hartman, Linda; Grabau, Dorthe; Fornander, Tommy; Malmström, Per; Nordenskjöld, Bo; Sgroi, Dennis C.; Skoog, Lambert; Stål, Olle; Leeb-Lundberg, L. M. Fredrik; Fernö, Mårten (May 2014). "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. doi:10.1007/s10549-014-2936-4. ISSN   1573-7217. PMID   24715381.
  49. Talia, Marianna; De Francesco, Ernestina Marianna; Rigiracciolo, Damiano Cosimo; Muoio, Maria Grazia; Muglia, Lucia; Belfiore, Antonino; Maggiolini, Marcello; Sims, Andrew H.; Lappano, Rosamaria (4 March 2020). "The G Protein-Coupled Estrogen Receptor (GPER) Expression Correlates with Pro-Metastatic Pathways in ER-Negative Breast Cancer: A Bioinformatics Analysis". Cells. 9 (3): 622. doi:10.3390/cells9030622. ISSN   2073-4409. PMC   7140398 . PMID   32143514.
  50. Xu, Ting; Ma, Ding; Chen, Sheng; Tang, Rui; Yang, Jianling; Meng, Chunhui; Feng, Yang; Liu, Li; Wang, Jiangfen; Luo, Haojun; Yu, Keda (30 August 2022). "High GPER expression in triple-negative breast cancer is linked to pro-metastatic pathways and predicts poor patient outcomes". NPJ breast cancer. 8 (1): 100. doi:10.1038/s41523-022-00472-4. ISSN   2374-4677. PMC   9427744 . PMID   36042244.
  51. 1 2 Sahin, Nilfer; Altun, Hatice; Kurutaş, Ergül Belge; Fındıklı, Ebru (20 May 2018). "Evaluation of estrogen and G protein-coupled estrogen receptor 1 (GPER) levels in drug-naïve patients with attention deficit hyperactivity disorder (ADHD)". Bosnian Journal of Basic Medical Sciences. 18 (2): 126–131. doi:10.17305/bjbms.2018.2942. ISSN   1840-4812. PMC   5988531 . PMID   29659348.
  52. Smith, Harriet O.; Arias-Pulido, Hugo; Kuo, Dennis Y.; Howard, Tamara; Qualls, Clifford R.; Lee, Sang-Joon; Verschraegen, Claire F.; Hathaway, Helen J.; Joste, Nancy E.; Prossnitz, Eric R. (September 2009). "GPR30 predicts poor survival for ovarian cancer". Gynecologic Oncology. 114 (3): 465–471. doi:10.1016/j.ygyno.2009.05.015. ISSN   1095-6859. PMC   2921775 . PMID   19501895.
  53. Chevalier, Nicolas; Vega, Aurélie; Bouskine, Adil; Siddeek, Bénazir; Michiels, Jean-François; Chevallier, Daniel; Fénichel, Patrick (2012). "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. doi:10.1371/journal.pone.0034672. ISSN   1932-6203. PMC   3319601 . PMID   22496838.
  54. Chan, Yu-Tzu; Lai, Alan C.-Y.; Lin, Ruey-Jen; Wang, Ya-Hui; Wang, Yi-Ting; Chang, Wen-Wei; Wu, Hsin-Yi; Lin, Yu-Ju; Chang, Wen-Ying; Wu, Jen-Chine; Yu, Jyh-Cherng; Chen, Yu-Ju; Yu, Alice L. (15 March 2020). "GPER-induced signaling is essential for the survival of breast cancer stem cells". International Journal of Cancer. 146 (6): 1674–1685. doi:10.1002/ijc.32588. ISSN   1097-0215. PMC   7003894 . PMID   31340060.
  55. Marjon, Nicole A.; Hu, Chelin; Hathaway, Helen J.; Prossnitz, Eric R. (November 2014). "G protein-coupled estrogen receptor regulates mammary tumorigenesis and metastasis". Molecular cancer research: MCR. 12 (11): 1644–1654. doi:10.1158/1541-7786.MCR-14-0128-T. ISSN   1557-3125. PMC   4233188 . PMID   25030371.
  56. Petrie, Whitney K.; Dennis, Megan K.; Hu, Chelin; Dai, Donghai; Arterburn, Jeffrey B.; Smith, Harriet O.; Hathaway, Helen J.; Prossnitz, Eric R. (2013). "G protein-coupled estrogen receptor-selective ligands modulate endometrial tumor growth". Obstetrics and Gynecology International. 2013: 472720. doi:10.1155/2013/472720. ISSN   1687-9589. PMC   3863501 . PMID   24379833.
  57. Natale, Christopher A.; Li, Jinyang; Pitarresi, Jason R.; Norgard, Robert J.; Dentchev, Tzvete; Capell, Brian C.; Seykora, John T.; Stanger, Ben Z.; Ridky, Todd W. (2020). "Pharmacologic Activation of the G Protein-Coupled Estrogen Receptor Inhibits Pancreatic Ductal Adenocarcinoma". Cellular and Molecular Gastroenterology and Hepatology. 10 (4): 868–880.e1. doi:10.1016/j.jcmgh.2020.04.016. ISSN   2352-345X. PMC   7578406 . PMID   32376419.
  58. Weißenborn, Christine; Ignatov, Tanja; Ochel, Hans-Joachim; Costa, Serban Dan; Zenclussen, Ana Claudia; Ignatova, Zoya; Ignatov, Atanas (May 2014). "GPER functions as a tumor suppressor in triple-negative breast cancer cells". Journal of Cancer Research and Clinical Oncology. 140 (5): 713–723. doi:10.1007/s00432-014-1620-8. ISSN   1432-1335. PMID   24553912.
  59. Liu, Qiao; Chen, Zhuojia; Jiang, Guanmin; Zhou, Yan; Yang, Xiangling; Huang, Hongbin; Liu, Huanliang; Du, Jun; Wang, Hongsheng (5 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. ISSN   1476-4598. PMC   5418684 . PMID   28476123.
  60. Roque, C.; Mendes-Oliveira, J.; Duarte-Chendo, C.; Baltazar, G. (October 2019). "The role of G protein-coupled estrogen receptor 1 on neurological disorders". Frontiers in Neuroendocrinology. 55: 100786. doi:10.1016/j.yfrne.2019.100786. ISSN   1095-6808. PMID   31513775. S2CID   202043731.

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