G protein-coupled estrogen receptor | G protein-coupled receptors

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G protein-coupled estrogen receptor

G protein-coupled estrogen receptor C

Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).

Overview

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The G protein-coupled estrogen receptor (GPER, nomenclature as agreed by the NC-IUPHAR Subcommittee on the G protein-coupled estrogen receptor [12]) was identified following observations of estrogen-evoked cyclic AMP signalling in breast cancer cells [1], which mirrored the differential expression of an orphan 7-transmembrane receptor GPR30 [3]. There are observations of both cell-surface and intracellular expression of the GPER receptor [14-15]. Selective agonist/ antagonists for GPER have been characterized [12]. Antagonists of the nuclear estrogen receptor, such as fulvestrant [7], tamoxifen [14-15] and raloxifene [11], as well as the flavonoid 'phytoestrogens' genistein and quercetin [9], are agonists of GPER. Reviews of GPER pharmacology have been published [12]. The roles of GPER in (patho)physiological systems throughout the body (cardiovascular, metabolic, endocrine, immune, reproductive) and in cancer have also been reviewed [6,8,10,12-13]. The GPER-selective agonist G-1 is currently in Phase I/II clinical trials for cancer (NCT04130516).

Receptors

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GPER C Show summary »« Hide summary More detailed page go icon to follow link

Target Id

221

Nomenclature

GPER

Previous and unofficial names

Genes

GPER1 (Hs), Gper1 (Mm), Gper1 (Rn)

Ensembl ID

ENSG00000164850 (Hs), ENSMUSG00000053647 (Mm), ENSRNOG00000001287 (Rn)

UniProtKB AC

Q99527 (Hs), Q8BMP4 (Mm), O08878 (Rn)

Principal transduction

G_i/G_o family

Endogenous agonists

17β-estradiol [14-15]

Agonists

fulvestrant [15]

raloxifene [11]

4-hydroxytamoxifen [14]

Selective agonists

G-1 [2]

Selective antagonists

G36 pIC₅₀ 6.8 – 6.9 [5]

G15 pIC₅₀ 6.7 [4]

Labelled ligands

[³H]17β-estradiol (Agonist) [15]

References

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1. Aronica SM, Kraus WL, Katzenellenbogen BS. (1994) Estrogen action via the cAMP signaling pathway: stimulation of adenylate cyclase and cAMP-regulated gene transcription. Proc Natl Acad Sci USA, 91 (18): 8517-21. [PMID:8078914]

2. Bologa CG, Revankar CM, Young SM, Edwards BS, Arterburn JB, Kiselyov AS, Parker MA, Tkachenko SE, Savchuck NP, Sklar LA et al.. (2006) Virtual and biomolecular screening converge on a selective agonist for GPR30. Nat Chem Biol, 2 (4): 207-12. [PMID:16520733]

3. Carmeci C, Thompson DA, Ring HZ, Francke U, Weigel RJ. (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. [PMID:9367686]

4. Dennis MK, Burai R, Ramesh C, Petrie WK, Alcon SN, Nayak TK, Bologa CG, Leitao A, Brailoiu E, Deliu E et al.. (2009) In vivo effects of a GPR30 antagonist. Nat Chem Biol, 5 (6): 421-7. [PMID:19430488]

5. Dennis MK, Field AS, Burai R, Ramesh C, Petrie WK, Bologa CG, Oprea TI, Yamaguchi Y, Hayashi S, Sklar LA et al.. (2011) Identification of a GPER/GPR30 antagonist with improved estrogen receptor counterselectivity. J Steroid Biochem Mol Biol, 127 (3-5): 358-66. [PMID:21782022]

6. Filardo EJ. (2018) A role for G-protein coupled estrogen receptor (GPER) in estrogen-induced carcinogenesis: Dysregulated glandular homeostasis, survival and metastasis. J Steroid Biochem Mol Biol, 176: 38-48. [PMID:28595943]

7. Filardo EJ, Quinn JA, Bland KI, Frackelton Jr AR. (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. Mol Endocrinol, 14 (10): 1649-60. [PMID:11043579]

8. Lappano R, Maggiolini M. (2018) GPER is involved in the functional liaison between breast tumor cells and cancer-associated fibroblasts (CAFs). J Steroid Biochem Mol Biol, 176: 49-56. [PMID:28249728]

9. Maggiolini M, Vivacqua A, Fasanella G, Recchia AG, Sisci D, Pezzi V, Montanaro D, Musti AM, Picard D, Andò S. (2004) The G protein-coupled receptor GPR30 mediates c-fos up-regulation by 17beta-estradiol and phytoestrogens in breast cancer cells. J Biol Chem, 279 (26): 27008-16. [PMID:15090535]

10. Meyer MR, Barton M. (2018) GPER blockers as Nox downregulators: A new drug class to target chronic non-communicable diseases. J Steroid Biochem Mol Biol, 176: 82-87. [PMID:28343901]

11. Petrie WK, Dennis MK, Hu C, Dai D, Arterburn JB, Smith HO, Hathaway HJ, Prossnitz ER. (2013) G protein-coupled estrogen receptor-selective ligands modulate endometrial tumor growth. Obstet Gynecol Int, 2013: 472720. [PMID:24379833]

12. Prossnitz ER, Arterburn JB. (2015) International Union of Basic and Clinical Pharmacology. XCVII. G Protein-Coupled Estrogen Receptor and Its Pharmacologic Modulators. Pharmacol Rev, 67 (3): 505-40. [PMID:26023144]

13. Prossnitz ER, Hathaway HJ. (2015) What have we learned about GPER function in physiology and disease from knockout mice?. J Steroid Biochem Mol Biol, 153: 114-26. [PMID:26189910]

14. Revankar CM, Cimino DF, Sklar LA, Arterburn JB, Prossnitz ER. (2005) A transmembrane intracellular estrogen receptor mediates rapid cell signaling. Science, 307 (5715): 1625-30. [PMID:15705806]

15. Thomas P, Pang Y, Filardo EJ, Dong J. (2005) Identity of an estrogen membrane receptor coupled to a G protein in human breast cancer cells. Endocrinology, 146 (2): 624-32. [PMID:15539556]

NC-IUPHAR subcommittee and family contributors

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How to cite this family page

Database page citation (select format):

Concise Guide to PHARMACOLOGY citation:

Alexander SP, Christopoulos A, Davenport AP, Kelly E, Mathie A, Peters JA, Veale EL et al. (2021) THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: G protein-coupled receptors. Br J Pharmacol. 176 Suppl 1:S27-S156.