The G-protein-coupled estrogen receptor (GPER, provisional nomenclature) was identified following observations of estrogen-evoked cAMP 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 [7-8].

Antagonists at the nuclear estrogen receptor, such as fulvestrant and tamoxifen [5], as well as the flavonoid ‘phytoestrogens’ genistein and quercetin [6], are agonists at GPER receptors.

Nilsson, BO; Olde, B; Leeb-Lundberg, LM. (2011) G protein-coupled oestrogen receptor 1 (GPER1)/GPR30: a new player in cardiovascular and metabolic oestrogenic signalling. Br. J. Pharmacol., 163 (6): 1131-9. [PMID:21250980]

Prossnitz, E.R., Arterburn, J.B., Smith, H.O., Oprea, T.I., Sklar, L.A. and Hathaway, H.J. (2008) Estrogen signaling through the transmembrane G protein-coupled receptor GPR30. Annu Rev Physiol, 70: 165-190. [PMID:18271749]

Prossnitz, E.R., Sklar, L.A., Oprea, T.I. and Arterburn, J.B. (2008) GPR30: a novel therapeutic target in estrogen-related disease. Trends Pharmacol Sci, 29: 116-123. [PMID:18262661]

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; Maggiolini, M. (2009) Mechanisms of estrogen signaling and gene expression via GPR30. Mol. Cell. Endocrinol., 308 (1-2): 32-8. [PMID:19464786]

Smith, HO; Arias-Pulido, H; Kuo, DY; Howard, T; Qualls, CR; Lee, SJ; Verschraegen, CF; Hathaway, HJ; Joste, NE; Prossnitz, ER. (2009) GPR30 predicts poor survival for ovarian cancer. Gynecol. Oncol., 114 (3): 465-71. [PMID:19501895]

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. U.S.A., 91 (18): 8517-21. [PMID:8078914]

2. Bologa, C. G., Revankar, C. M., Young, S. M., Edwards, B. S., Arterburn, J. B., Kiselyov, A. S., Parker, M. A., Tkachenko, S. E., Savchuck, N. P., Sklar, L. A., Oprea, T. I. and Prossnitz, E. R. (2006) Virtual and biomolecular screening converge on a selective agonist for GPR30. Nat Chem Biol, 2: 207-212. [PMID:16520733]

3. Carmeci, C., Thompson, D. A., Ring, H. Z., Francke, U. and Weigel, R. J. (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: 607-617. [PMID:9367686]

4. Dennis, M.K., Burai, R., Ramesh, C., Petrie, W.K., Alcon, S.N., Nayak, T.K., Bologa, C.G., Leitao, A., Brailoiu, E., Deliu, E., Dun, N.J., Sklar, L.A., Hathaway, H.J., Arterburn, J.B., Oprea, T.I. and Prossnitz, E.R. (2009) In vivo effects of a GPR30 antagonist. Nat Chem Biol, 5: 421-427. [PMID:19430488]

5. Filardo, E. J., Quinn, J. A., Bland, K. I. and Frackelton, A. R. (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: 1649-1660. [PMID:11043579]

6. Maggiolini, M., Vivacqua, A., Fasanella, G., Recchia, A. G., Sisci, D., Pezzi, V., Montanaro, D., Musti, A. M., Picard, D. and 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: 27008-27016. [PMID:15090535]

7. Revankar, C. M., Cimino, D. F., Sklar, L. A., Arterburn, J. B. and Prossnitz, E. R. (2005) A transmembrane intracellular estrogen receptor mediates rapid cell signaling. Science, 307: 1625-1630. [PMID:15705806]

8. Thomas, P., Pang, Y., Filardo, E. J. and Dong, J. (2005) Identity of an estrogen membrane receptor coupled to a G protein in human breast cancer cells. Endocrinology, 146: 624-632. [PMID:15539556]