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).

* Key recommended reading is highlighted with an asterisk

* Arterburn JB, Prossnitz ER. (2023) G Protein-Coupled Estrogen Receptor GPER: Molecular Pharmacology and Therapeutic Applications. Annu Rev Pharmacol Toxicol, 63: 295-320. [PMID:36662583]

Barton M. (2012) Position paper: The membrane estrogen receptor GPER--Clues and questions. Steroids, 77 (10): 935-42. [PMID:22521564]

* Barton M, Filardo EJ, Lolait SJ, Thomas P, Maggiolini M, Prossnitz ER. (2018) Twenty years of the G protein-coupled estrogen receptor GPER: Historical and personal perspectives. J Steroid Biochem Mol Biol, 176: 4-15. [PMID:28347854]

Barton M, Prossnitz ER. (2015) Emerging roles of GPER in diabetes and atherosclerosis. Trends Endocrinol Metab, 26 (4): 185-92. [PMID:25767029]

Filardo EJ, Thomas P. (2012) Minireview: G protein-coupled estrogen receptor-1, GPER-1: its mechanism of action and role in female reproductive cancer, renal and vascular physiology. Endocrinology, 153 (7): 2953-62. [PMID:22495674]

* Gaudet HM, Cheng SB, Christensen EM, Filardo EJ. (2015) The G-protein coupled estrogen receptor, GPER: The inside and inside-out story. Mol Cell Endocrinol, 418 Pt 3: 207-19. [PMID:26190834]

Han G, Li F, Yu X, White RE. (2013) GPER: a novel target for non-genomic estrogen action in the cardiovascular system. Pharmacol Res, 71: 53-60. [PMID:23466742]

Lappano R, Pisano A, Maggiolini M. (2014) GPER Function in Breast Cancer: An Overview. Front Endocrinol (Lausanne), 5: 66. [PMID:24834064]

* 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]

Prossnitz ER, Barton M. (2009) Signaling, physiological functions and clinical relevance of the G protein-coupled estrogen receptor GPER. Prostaglandins Other Lipid Mediat, 89 (3-4): 89-97. [PMID:19442754]

Prossnitz ER, Barton M. (2011) The G-protein-coupled estrogen receptor GPER in health and disease. Nat Rev Endocrinol, 7 (12): 715-26. [PMID:21844907]

Prossnitz ER, Barton M. (2014) Estrogen biology: new insights into GPER function and clinical opportunities. Mol Cell Endocrinol, 389 (1-2): 71-83. [PMID:24530924]

* Prossnitz ER, Barton M. (2023) The G protein-coupled oestrogen receptor GPER in health and disease: an update. Nat Rev Endocrinol, 19 (7): 407-424. [PMID:37193881]

* 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]

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]

Subcommittee members: Eric R. Prossnitz (Chairperson) Department of Internal Medicine University of New Mexico Health Sciences Center 2325 Camino de Salud NE Albuquerque, NM 87131 United States

Other contributors: Edward J. Filardo Professor of Surgical Oncology Member, Holden Comprehensive Cancer Center University of Iowa 500 Newton Street, MERF 4206 Iowa City, IA 52242 USA