General

G-Protein-coupled Estrogen Receptor (GPER) [16], previously assigned a standard orphan receptor designation and referred to as GPR30, was associated with estrogen action by experiments that showed that GPER expression was required for estrogen-mediated transactivation of the epidermal growth factor receptor [7] and stimulation of adenylyl cyclase [8]. Additional evidence that GPER functions as a cognate receptor for estrogen has been provided by results linking its expression to specific binding [19,23].

GPER is a seven transmembrane spanning receptor that couples to heterotrimeric G_s-proteins and functions autonomously from ERα or ERβ estrogen receptors (members of the steroid hormone receptor family) based on the following: First, GPER is encoded by a unique gene that maps to chromosome 7p22 [3]. Second, GPER selective agonists [2] and antagonists [4-5] have been developed that further discriminate ER and GPER function. GPER expression promotes estrogen action in cells that do not express ERs [7]. Third, estrogen-like compounds that function as ER antagonists (Tamoxifen, Faslodex and Raloxifene), promote GPER-mediated action [7-8,15-16,19]. In addition, GPER and ER assort independently from one another in human breast tumors and each receptor type independently associates with tumor progression variables [6]. Similarly, GPER expression is positively associated with poor survival in endometrial and ovarian cancer [21]. Moreover, GPER-deficient mice [17] exhibit altered thymic function as well as glucose tolerance, blood pressure, and bone growth [14,20,24-25].

Finally, emerging data indicates that estrogen action through ER or GPER results in distinct cell biological activities. ER clearly manifests the potent mitogenic effects of estrogen. By comparison, GPER promotes a modest proliferative effect [1] and is linked to anti-apoptotic signaling [11,18,26], consistent with biological activities promoted by members of the seven transmembrane spanning receptor superfamily. Some discussion remains regarding the independent role of GPER in estrogen action [10]. Recent results point to a novel role for GPER in regulating the expression of NADPH oxidase 1 (NOX1; Q9Y5S8), being essential for ROS production in the cardiovascular system, and hence critical to hypertension, cardiovascular disease and aging [13].

For comprehensive discussions on the structure, function and pharmacology of GPER as an alternative membrane estrogen receptor, we call your attention to numerous reviews and research perspectives in the following articles- [9,12,16-17,22].

1. Albanito L, Madeo A, Lappano R, Vivacqua A, Rago V, Carpino A, Oprea TI, Prossnitz ER, Musti AM, Andò S et al.. (2007) G protein-coupled receptor 30 (GPR30) mediates gene expression changes and growth response to 17beta-estradiol and selective GPR30 ligand G-1 in ovarian cancer cells. Cancer Res, 67 (4): 1859-66. [PMID:17308128]

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, Graeber CT, Quinn JA, Resnick MB, Giri D, DeLellis RA, Steinhoff MM, Sabo E. (2006) Distribution of GPR30, a seven membrane-spanning estrogen receptor, in primary breast cancer and its association with clinicopathologic determinants of tumor progression. Clin Cancer Res, 12 (21): 6359-66. [PMID:17085646]

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. Filardo EJ, Quinn JA, Frackelton Jr AR, Bland KI. (2002) Estrogen action via the G protein-coupled receptor, GPR30: stimulation of adenylyl cyclase and cAMP-mediated attenuation of the epidermal growth factor receptor-to-MAPK signaling axis. Mol Endocrinol, 16 (1): 70-84. [PMID:11773440]

9. 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]

10. Isensee J, Meoli L, Zazzu V, Nabzdyk C, Witt H, Soewarto D, Effertz K, Fuchs H, Gailus-Durner V, Busch D et al.. (2009) Expression pattern of G protein-coupled receptor 30 in LacZ reporter mice. Endocrinology, 150 (4): 1722-30. [PMID:19095739]

11. Kanda N, Watanabe S. (2003) 17beta-estradiol inhibits oxidative stress-induced apoptosis in keratinocytes by promoting Bcl-2 expression. J Invest Dermatol, 121 (6): 1500-9. [PMID:14675202]

12. Manavathi B, Kumar R. (2006) Steering estrogen signals from the plasma membrane to the nucleus: two sides of the coin. J Cell Physiol, 207: 594-604. [PMID:16270355]

13. Meyer MR, Fredette NC, Daniel C, Sharma G, Amann K, Arterburn JB, Barton M, Prossnitz ER. (2016) Obligatory role for GPER in cardiovascular aging and disease. Sci Signal, 9 (452): ra105. [PMID:27803283]

14. Mårtensson UE, Salehi SA, Windahl S, Gomez MF, Swärd K, Daszkiewicz-Nilsson J, Wendt A, Andersson N, Hellstrand P, Grände PO et al.. (2009) Deletion of the G protein-coupled receptor 30 impairs glucose tolerance, reduces bone growth, increases blood pressure, and eliminates estradiol-stimulated insulin release in female mice. Endocrinology, 150 (2): 687-98. [PMID:18845638]

15. 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]

16. 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]

17. 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]

18. Quinn JA, Graeber CT, Frackelton Jr AR, Kim M, Schwarzbauer JE, Filardo EJ. (2009) Coordinate regulation of estrogen-mediated fibronectin matrix assembly and epidermal growth factor receptor transactivation by the G protein-coupled receptor, GPR30. Mol Endocrinol, 23 (7): 1052-64. [PMID:19342448]

19. 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]

20. Sharma G, Hu C, Brigman JL, Zhu G, Hathaway HJ, Prossnitz ER. (2013) GPER deficiency in male mice results in insulin resistance, dyslipidemia, and a proinflammatory state. Endocrinology, 154 (11): 4136-45. [PMID:23970785]

21. 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]

22. Terasawa E, Noel SD, Keen KL. (2009) Rapid action of oestrogen in luteinising hormone-releasing hormone neurones: the role of GPR30. J Neuroendocrinol, 21 (4): 316-21. [PMID:19207808]

23. 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]

24. Wang C, Dehghani B, Magrisso IJ, Rick EA, Bonhomme E, Cody DB, Elenich LA, Subramanian S, Murphy SJ, Kelly MJ et al.. (2008) GPR30 contributes to estrogen-induced thymic atrophy. Mol Endocrinol, 22 (3): 636-48. [PMID:18063692]

25. Windahl SH, Andersson N, Chagin AS, Mårtensson UE, Carlsten H, Olde B, Swanson C, Movérare-Skrtic S, Sävendahl L, Lagerquist MK et al.. (2009) The role of the G protein-coupled receptor GPR30 in the effects of estrogen in ovariectomized mice. Am J Physiol Endocrinol Metab, 296 (3): E490-6. [PMID:19088255]

26. Zekas E, Prossnitz ER. (2015) Estrogen-mediated inactivation of FOXO3a by the G protein-coupled estrogen receptor GPER. BMC Cancer, 15: 702. [PMID:26470790]