Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The G-protein-coupled estrogen receptor GPER in health and disease

Nature Reviews Endocrinology volume 7, pages 715–726 (2011)Cite this article

Subjects

Abstract

Estrogens mediate profound effects throughout the body and regulate physiological and pathological processes in both women and men. The low prevalence of many diseases in premenopausal women is attributed to the presence of 17β-estradiol, the predominant and most potent endogenous estrogen. In addition to endogenous estrogens, several man-made and plant-derived molecules, such as bisphenol A and genistein, also exhibit estrogenic activity. Traditionally, the actions of 17β-estradiol are ascribed to two nuclear estrogen receptors (ERs), ERα and ERβ, which function as ligand-activated transcription factors. However, 17β-estradiol also mediates rapid signaling events via pathways that involve transmembrane ERs, such as G-protein-coupled ER 1 (GPER; formerly known as GPR30). In the past 10 years, GPER has been implicated in both rapid signaling and transcriptional regulation. With the discovery of GPER-selective ligands that can selectively modulate GPER function in vitro and in preclinical studies and with the use of Gper knockout mice, many more potential roles for GPER are being elucidated. This Review highlights the physiological roles of GPER in the reproductive, nervous, endocrine, immune and cardiovascular systems, as well as its pathological roles in a diverse array of disorders including cancer, for which GPER is emerging as a novel therapeutic target and prognostic indicator.

Key Points

  • Estrogen has critical nonreproductive roles in health, including beneficial effects on the skeletal, nervous, endocrine, immune and cardiovascular systems, as well as on many diseases and cancers

  • The estrogen receptors (ERs) include ERα, ERβ and G-protein-coupled estrogen receptor 1 (GPER); their expression and signaling mechanisms are complex and potentially exhibit redundant, independent, synergistic and/or antagonistic actions

  • Estrogenic compounds (selective ER modulators, ER antagonists, selective ER downregulators, phytoestrogens and xenoestrogens) have multifaceted effects on all types of ERs with receptor-specific pharmacological profiles

  • GPER-selective agonists, such as G-1, mediate many salutary effects of estrogen in various tissues and organs with only minor reproductive effects

  • GPER represents an important diagnostic, prognostic and therapeutic target; development of GPER-selective agonists and antagonists could contribute to the diagnosis and treatment of many diseases

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Structures of selective and nonselective estrogen receptor ligands.
Figure 2: Nongenomic and genomic estrogen signaling pathways.
Figure 3: Involvement of G-protein-coupled estrogen receptor (GPER) action in regulation of physiological responses and disease.

Similar content being viewed by others

References

  1. Hess, R. A. Estrogen in the adult male reproductive tract: a review. Reprod. Biol. Endocrinol. 1, 52 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Deroo, B. J. & Korach, K. S. Estrogen receptors and human disease. J. Clin. Invest. 116, 561–570 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Prossnitz, E. R. et al. Estrogen signaling through the transmembrane G-protein-coupled receptor GPR30. Annu. Rev. Physiol. 70, 165–190 (2008).

    Article  CAS  PubMed  Google Scholar 

  4. Edwards, D. P. Regulation of signal transduction pathways by estrogen and progesterone. Annu. Rev. Physiol. 67, 335–376 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. Lorand, T., Vigh, E. & Garai, J. Hormonal action of plant derived and anthropogenic non-steroidal estrogenic compounds: phytoestrogens and xenoestrogens. Curr. Med. Chem. 17, 3542–3574 (2010).

    Article  CAS  PubMed  Google Scholar 

  6. Talwar, G. P., Segal, S. J., Evans, A. & Davidson,O. W. The binding of estradiol in the uterus: A mechanism for depression of RNA synthesis. Proc. Natl Acad. Sci. USA 52, 1059–1066 (1964).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Soloff, M. S. & Szego, C. M. Purification of estradiol receptor from rat uterus and blockade of its estrogen-binding function by specific antibody. Biochem. Biophys. Res. Commun. 34, 141–147 (1969).

    Article  CAS  PubMed  Google Scholar 

  8. Kuiper, G. G., Enmark, E., Pelto-Huikko, M., Nilsson, S. & Gustafsson, J. A. Cloning of a novel receptor expressed in rat prostate and ovary. Proc. Natl Acad. Sci. USA 93, 5925–5930 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Carroll, J. S. & Brown, M. Estrogen receptor target gene: an evolving concept. Mol. Endocrinol. 20, 1707–1714 (2006).

    Article  CAS  PubMed  Google Scholar 

  10. Hewitt, S. C. & Korach, K. S. Oestrogen receptor knockout mice: roles for oestrogen receptors α and β in reproductive tissues. Reproduction 1 25, 143–149 (2003).

    Article  Google Scholar 

  11. Hammes, S. R. & Levin, E. R. Extranuclear steroid receptors: nature and actions. Endocr. Rev. 28, 726–741 (2007).

    Article  CAS  PubMed  Google Scholar 

  12. Pietras, R. J. & Szego, C. M. Endometrial cell calcium and oestrogen action. Nature 253, 357–359 (1975).

    Article  CAS  PubMed  Google Scholar 

  13. Pietras, R. J. & Szego, C. M. Specific binding sites for oestrogen at the outer surfaces of isolated endometrial cells. Nature 265, 69–72 (1977).

    Article  CAS  PubMed  Google Scholar 

  14. Szego, C. M. & Davis, J. S. Adenosine 3′, 5′-monophosphate in rat uterus: acute elevation by estrogen. Proc. Natl Acad. Sci. USA 58, 1711–1718 (1967).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Wehling, M. Looking beyond the dogma of genomic steroid action: insights and facts of the 1990s. J. Mol. Med. 73, 439–447 (1995).

    Article  CAS  PubMed  Google Scholar 

  16. Wehling, M. Specific, nongenomic actions of steroid hormones. Annu. Rev. Physiol. 59, 365–393 (1997).

    Article  CAS  PubMed  Google Scholar 

  17. Filardo, E. J., Quinn, J. A., Bland, K. I. & Frackelton, A. R. Jr. Estrogen-induced activation of Erk1 and Erk2 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 (2000).

    Article  CAS  PubMed  Google Scholar 

  18. Carmeci, C., Thompson, D. A., Ring, H. Z., Francke, U. & Weigel, R. J. 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 (1997).

    Article  CAS  PubMed  Google Scholar 

  19. Feng, Y. & Gregor, P. Cloning of a novel member of the G-protein-coupled receptor family related to peptide receptors. Biochem. Biophys. Res. Commun. 231, 651–654 (1997).

    Article  CAS  PubMed  Google Scholar 

  20. Kvingedal, A. M. & Smeland, E. B. A novel putative G-protein-coupled receptor expressed in lung, heart and lymphoid tissue. FEBS Lett. 407, 59–62 (1997).

    Article  CAS  PubMed  Google Scholar 

  21. O'Dowd, B. F. et al. Discovery of three novel G-protein-coupled receptor genes. Genomics 47, 310–313 (1998).

    Article  CAS  PubMed  Google Scholar 

  22. Owman, C., Blay, P., Nilsson, C. & Lolait, S. J. Cloning of human cDNA encoding a novel heptahelix receptor expressed in Burkitt's lymphoma and widely distributed in brain and peripheral tissues. Biochem. Biophys. Res. Commun. 228, 285–292 (1996).

    Article  CAS  PubMed  Google Scholar 

  23. Takada, Y., Kato, C., Kondo, S., Korenaga, R. & Ando, J. Cloning of cDNAs encoding G-protein-coupled receptor expressed in human endothelial cells exposed to fluid shear stress. Biochem. Biophys. Res. Commun. 2 40, 737–741 (1997).

    Article  Google Scholar 

  24. Filardo, E. J., Quinn, J. A., Frackelton, A. R. Jr & Bland, K. I. 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, 70–84 (2002).

    Article  CAS  PubMed  Google Scholar 

  25. Kanda, N. & Watanabe, S. 17β-estradiol inhibits oxidative stress-induced apoptosis in keratinocytes by promoting Bcl-2 expression. J. Invest. Dermatol. 121, 1500–1509 (2003).

    Article  CAS  PubMed  Google Scholar 

  26. Kanda, N. & Watanabe, S. 17β-estradiol enhances the production of nerve growth factor in THP-1-derived macrophages or peripheral blood monocyte-derived macrophages. J. Invest. Dermatol. 12 1, 771–780 (2003).

    Article  Google Scholar 

  27. Kanda, N. & Watanabe, S. 17β-estradiol stimulates the growth of human keratinocytes by inducing cyclin D2 expression. J. Invest. Dermatol. 123, 319–328 (2004).

    Article  CAS  PubMed  Google Scholar 

  28. Maggiolini, M. et al. The G-protein-coupled receptor GPR30 mediates c-fos up-regulation by 17β-estradiol and phytoestrogens in breast cancer cells. J. Biol. Chem. 279, 27008–27016 (2004).

    Article  CAS  PubMed  Google Scholar 

  29. Ahola, T. M., Alkio, N., Manninen, T. & Ylikomi, T. Progestin and G-protein-coupled receptor 30 inhibit mitogen-activated protein kinase activity in MCF-7 breast cancer cells. Endocrinology 143, 4620–4626 (2002).

    Article  CAS  PubMed  Google Scholar 

  30. Ahola, T. M., Manninen, T., Alkio, N. & Ylikomi, T. G-protein-coupled receptor 30 is critical for a progestin-induced growth inhibition in MCF-7 breast cancer cells. Endocrinology 143, 3376–3384 (2002).

    Article  CAS  PubMed  Google Scholar 

  31. Ahola, T. M. et al. Progestin upregulates G-protein-coupled receptor 30 in breast cancer cells. Eur. J. Biochem. 269, 2485–2490 (2002).

    Article  CAS  PubMed  Google Scholar 

  32. Thomas, P., Pang, Y., Filardo, E. J. & Dong, J. Identity of an estrogen membrane receptor coupled to a G protein in human breast cancer cells. Endocrinology 146, 624–632 (2005).

    Article  CAS  PubMed  Google Scholar 

  33. Revankar, C. M., Cimino, D. F., Sklar, L. A., Arterburn, J. B. & Prossnitz, E. R. A transmembrane intracellular estrogen receptor mediates rapid cell signaling. Science 30 7, 1625–1630 (2005).

    Article  CAS  Google Scholar 

  34. Olde, B. & Leeb-Lundberg, L. M. GPR30/GPER1: searching for a role in estrogen physiology. Trends Endocrinol. Metab. 20, 409–416 (2009).

    Article  CAS  PubMed  Google Scholar 

  35. Boon, W. C., Chow, J. D. & Simpson, E. R. The multiple roles of estrogens and the enzyme aromatase. Prog. Brain Res. 181, 209–232 (2010).

    Article  CAS  PubMed  Google Scholar 

  36. Lappano, R. et al. Estriol acts as a GPR30 antagonist in estrogen receptor-negative breast cancer cells. Mol. Cell. Endocrinol. 320, 162–170 (2010).

    Article  CAS  PubMed  Google Scholar 

  37. Pasqualini, J. R., Gelly, C., Nguyen, B. L. & Vella, C. Importance of estrogen sulfates in breast cancer. J. Steroid Biochem. 34, 155–163 (1989).

    Article  CAS  PubMed  Google Scholar 

  38. Geisler, J. Breast cancer tissue estrogens and their manipulation with aromatase inhibitors and inactivators. J. Steroid Biochem. Mol. Biol. 86, 245–253 (2003).

    Article  CAS  PubMed  Google Scholar 

  39. Diczfalusky, E. & Mancuso, S. in Foetus and Placenta (eds. Klopper, A. & Diczfalusky, E) (Blackwell, Oxford, 1969).

    Google Scholar 

  40. Muller, R. E., Johnston, T. C., Traish, A. M. & Wotiz, H. H. Studies on the mechanism of estradiol uptake by rat uterine cells and on estradiol binding to uterine plasma membranes. Adv. Exp. Med. Biol. 1 17, 401–421 (1979).

    Article  Google Scholar 

  41. Ososki, A. L. & Kennelly, E. J. Phytoestrogens: a review of the present state of research. Phytother. Res. 17, 845–869 (2003).

    Article  CAS  PubMed  Google Scholar 

  42. Starek, A. Estrogens and organochlorine xenoestrogens and breast cancer risk. Int. J. Occup. Med. Environ. Health 16, 113–124 (2003).

    PubMed  Google Scholar 

  43. Singleton, D. W. & Khan, S. A. Xenoestrogen exposure and mechanisms of endocrine disruption. Front. Biosci. 8, s110–s118 (2003).

    Article  CAS  PubMed  Google Scholar 

  44. Morton, M. S., Arisaka, O., Miyake, N., Morgan, L. D. & Evans, B. A. Phytoestrogen concentrations in serum from Japanese men and women over forty years of age. J. Nutr. 132, 3168–3171 (2002).

    Article  CAS  PubMed  Google Scholar 

  45. Thomas, P. & Dong, J. Binding and activation of the seven-transmembrane estrogen receptor GPR30 by environmental estrogens: a potential novel mechanism of endocrine disruption. J. Steroid Biochem. Mol. Biol. 102, 175–179 (2006).

    Article  CAS  PubMed  Google Scholar 

  46. Chevalier, N., Bouskine, A. & Fenichel, P. Bisphenol A promotes testicular seminoma cell proliferation through GPER, the G-protein-coupled estrogen receptor. Int. J. Cancer doi:10.1002/ijc.25972.

  47. Albanito, L. et al. G-protein-coupled receptor 30 and estrogen receptor a are involved in the proliferative effects induced by atrazine in ovarian cancer cells. Environ. Health Perspect. 116, 1648–1655 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Setchell, K. D. & Clerici, C. Equol: history, chemistry, and formation. J. Nutr. 140, 1355S–1362S (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Rowlands, D. J., Chapple, S., Siow, R. C. & Mann, G. E. Equol-stimulated mitochondrial reactive oxygen species activate endothelial nitric oxide synthase and redox signaling in endothelial cells: Roles for F-actin and GPR30. Hypertension 57, 833–840 (2011).

    Article  CAS  PubMed  Google Scholar 

  50. Jordan, V. C. SERMs: meeting the promise of multifunctional medicines. J. Natl Cancer Inst. 9 9, 350–356 (2007).

    Article  CAS  Google Scholar 

  51. Orlando, L. et al. Molecularly targeted endocrine therapies for breast cancer. Cancer Treat. Rev. 36 (Suppl. 3), S67–S71 (2011).

    Google Scholar 

  52. Fitts, J. M., Klein, R. M. & Powers, C. A. Tamoxifen regulation of bone growth and endocrine function in the ovariectomized rat: Discrinimation of responses involving ERα/ERβ, GPER or ERRgamma using fulvestrant (ICI 182, 780). J. Pharm. Exp. Ther. 338, 246–254 (2011).

    Article  CAS  Google Scholar 

  53. Albanito, L. et al. G-protein-coupled receptor 30 (GPR30) mediates gene expression changes and growth response to 17β-estradiol and selective GPR30 ligand G-1 in ovarian cancer cells. Cancer Res. 67, 1859–1866 (2007).

    Article  CAS  PubMed  Google Scholar 

  54. Dennis, M. K. et al. Identification of a GPER/GPR30 antagonist with improved estrogen receptor counterselectivity. J. Steroid Biochem. Mol. Biol. doi:10.1016/j.jsbmb.2011.07.002.

  55. Blasko, E. et al. Beneficial role of the GPR30 agonist G-1 in an animal model of multiple sclerosis. J. Neuroimmunol. 214, 67–77 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Wang, C. et al. Membrane estrogen receptor regulates experimental autoimmune encephalomyelitis through up-regulation of programmed death 1. J. Immunol. 182, 3294–3303 (2009).

    Article  CAS  PubMed  Google Scholar 

  57. Liu, S. et al. Importance of extranuclear estrogen receptor α and membrane G-protein-coupled estrogen receptor in pancreatic islet survival. Diabetes 58, 2292–2302 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Haas, E. et al. Regulatory role of G-protein-coupled estrogen receptor for vascular function and obesity. Circ. Res. 104, 288–291 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Dennis, M. K. et al. In vivo effects of a GPR30 antagonist. Nat. Chem. Biol. 5, 421–427 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Jenei-Lanzl, Z. et al. Estradiol inhibits chondrogenic differentiation of mesenchymal stem cells via nonclassic signaling. Arthritis Rheum. 62, 1088–1096 (2011).

    Article  CAS  Google Scholar 

  61. Lindsey, S. H., Carver, K. A., Prossnitz, E. R. & Chappell, M. C. Vasodilation in response to the GPR30 agonist G-1 is not different from estradiol in the mRen2.Lewis female rat. J. Cardiovasc. Pharmacol. 57, 598–603 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Peyton, C. & Thomas, P. Involvement of epidermal growth factor receptor signaling in estrogen inhibition of oocyte maturation mediated through the G-protein-coupled estrogen receptor (GPER) in zebrafish (Danio rerio). Biol. Reprod. 85, 42–50 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Gingerich, S. et al. Estrogen receptor α and G-protein-coupled receptor 30 mediate the neuroprotective effects of 17β-estradiol in novel murine hippocampal cell models. Neuroscience 170, 54–66 (2010).

    Article  CAS  PubMed  Google Scholar 

  64. Nayak, T. et al. Influence of charge on cell permeability and tumor imaging of GPR30-targeted 111in-labeled non-steroidal imaging agents. ACS Chem. Biol. 5, 681–690 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Ramesh, C. et al. Synthesis and characterization of iodinated tetrahydroquinolines targeting the G-protein-coupled estrogen receptor GPR30. J. Med. Chem. 53, 1004–1014 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Levin, E. R. Minireview: extranuclear steroid receptors: roles in modulation of cell functions. Mol. Endocrinol. 25, 377–384 (2011).

    Article  CAS  PubMed  Google Scholar 

  67. Otto, C. et al. GPR30 localizes to the endoplasmic reticulum and is not activated by estradiol. Endocrinology 149, 4846–4856 (2008).

    Article  CAS  PubMed  Google Scholar 

  68. Sanden, C. et al. G-protein-coupled estrogen receptor 1/G-protein-coupled receptor 30 localizes in the plasma membrane and traffics intracellularly on cytokeratin intermediate filaments. Mol. Pharmacol. 79, 400–410 (2011).

    Article  CAS  PubMed  Google Scholar 

  69. Cheng, S. B., Graeber, C. T., Quinn, J. A. & Filardo, E. J. Retrograde transport of the transmembrane estrogen receptor, G-protein-coupled receptor 30 (GPR30/GPER) from the plasma membrane towards the nucleus. Steroids 76, 892–896 (2011).

    CAS  PubMed  Google Scholar 

  70. Bhola, N. E. & Grandis, J. R. Crosstalk between G-protein-coupled receptors and epidermal growth factor receptor in cancer. Front. Biosci. 13, 1857–1865 (2008).

    Article  CAS  PubMed  Google Scholar 

  71. Prenzel, N. et al. EGF receptor transactivation by G-protein-coupled receptors requires metalloproteinase cleavage of proHB-EGF. Nature 402, 884–888 (1999).

    Article  CAS  PubMed  Google Scholar 

  72. Edwin, F. et al. A historical perspective of the EGF receptor and related systems. Methods Mol. Biol. 32 7, 1–24 (2006).

    Google Scholar 

  73. Ariazi, E. A. et al. The G-protein-coupled receptor GPR30 inhibits proliferation of estrogen receptor-positive breast cancer cells. Cancer Res. 70, 1184–1194 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Brailoiu, E. et al. Distribution and characterization of estrogen receptor G-protein-coupled receptor 30 in the rat central nervous system. J. Endocrinol. 193, 311–321 (2007).

    Article  CAS  PubMed  Google Scholar 

  75. Sukocheva, O. et al. Estrogen transactivates EGFR via the sphingosine 1-phosphate receptor Edg-3: the role of sphingosine kinase-1. J. Cell Biol. 173, 301–310 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Quinn, J. A. et al. Coordinate regulation of estrogen-mediated fibronectin matrix assembly and epidermal growth factor receptor transactivation by the G-protein-coupled receptor, GPR30. Mol. Endocrinol. 23, 1052–1064 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Meyer, M. R., Haas, E., Prossnitz, E. R. & Barton, M. Non-genomic regulation of vascular cell function and growth by estrogen. Mol. Cell Endocrinol. 308, 9–16 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Lin, B. C. et al. Stimulating the GPR30 estrogen receptor with a novel tamoxifen analogue activates SF-1 and promotes endometrial cell proliferation. Cancer Res. 69, 5415–5423 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Maggiolini, M. & Picard, D. The unfolding stories of GPR30, a new membrane-bound estrogen receptor. J. Endocrinol. 204, 105–114 (2010).

    Article  CAS  PubMed  Google Scholar 

  80. Prossnitz, E. R. & Maggiolini, M. Mechanisms of estrogen signaling and gene expression via GPR30. Mol. Cell Endocrinol. 30 8, 32–38 (2009).

    Article  CAS  Google Scholar 

  81. Isensee, J. et al. Expression pattern of G-protein-coupled receptor 30 in LacZ reporter mice. Endocrinology 150, 1722–1730 (2009).

    Article  CAS  PubMed  Google Scholar 

  82. Martensson, U. E. et al. 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, 687–698 (2009).

    Article  CAS  PubMed  Google Scholar 

  83. Otto, C. et al. GPR30 does not mediate estrogenic responses in reproductive organs in mice. Biol. Reprod. 80, 34–41 (2009).

    Article  CAS  PubMed  Google Scholar 

  84. Wang, C. et al. GPR30 contributes to estrogen-induced thymic atrophy. Mol. Endocrinol. 22, 636–648 (2008).

    Article  CAS  PubMed  Google Scholar 

  85. Hewitt, S. C., Harrell, J. C. & Korach, K. S. Lessons in estrogen biology from knockout and transgenic animals. Annu. Rev. Physiol. 67, 285–308 (2005).

    Article  CAS  PubMed  Google Scholar 

  86. Gao, F., Ma, X., Ostmann, A. B. & Das, S. K. GPR30 activation opposes estrogen-dependent uterine growth via inhibition of stromal ERK1/2 and estrogen receptor alpha (ERα) phosphorylation signals. Endocrinology 1 52, 1434–1447 (2011).

    Article  CAS  Google Scholar 

  87. Pang, Y., Dong, J. & Thomas, P. Estrogen signaling characteristics of Atlantic croaker G-protein-coupled receptor 30 (GPR30) and evidence it is involved in maintenance of oocyte meiotic arrest. Endocrinology 149, 3410–3426 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Wang, C., Prossnitz, E. R. & Roy, S. K. Expression of GPR30 in the hamster ovary: differential regulation by gonadotropins and steroid hormones. Endocrinology 148, 4853–4864 (2007).

    Article  CAS  PubMed  Google Scholar 

  89. Wang, C., Prossnitz, E. R. & Roy, S. K. G-protein-coupled receptor 30 expression is required for estrogen stimulation of primordial follicle formation in the hamster ovary. Endocrinology 149, 4452–4461 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Maiti, K. et al. G-1-activated membrane estrogen receptors mediate increased contractility of the human myometrium. Endocrinology 152, 2448–2455 (2011).

    Article  CAS  PubMed  Google Scholar 

  91. Chimento, A. et al. GPER and ESRs are expressed in rat round spermatids and mediate oestrogen-dependent rapid pathways modulating expression of cyclin B1 and Bax. Int. J. Androl. doi:10.1111/j.1365-2605.2010.01100.x.

  92. Chimento, A. et al. 17β-estradiol activates rapid signaling pathways involved in rat pachytene spermatocytes apoptosis through GPR30 and ERα. Mol. Cell. Endocrinol. 320, 136–144 (2010).

    Article  CAS  PubMed  Google Scholar 

  93. Sirianni, R. et al. The novel estrogen receptor, G-protein-coupled receptor 30, mediates the proliferative effects induced by 17β-estradiol on mouse spermatogonial GC-1 cell line. Endocrinology 149, 5043–5051 (2008).

    Article  CAS  PubMed  Google Scholar 

  94. Dun, S. L. et al. Expression of estrogen receptor GPR30 in the rat spinal cord and in autonomic and sensory ganglia. J. Neurosci. Res. 87, 1610–1619 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Hazell, G. G. et al. Localisation of GPR30, a novel G-protein-coupled oestrogen receptor, suggests multiple functions in rodent brain and peripheral tissues. J. Endocrinol. 202, 223–236 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Liverman, C. S., Brown, J. W., Sandhir, R., McCarson, K. E. & Berman, N. E. Role of the oestrogen receptors GPR30 and ERα in peripheral sensitization: relevance to trigeminal pain disorders in women. Cephalalgia 29, 729–741 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Kuhn, J. et al. GPR30 estrogen receptor agonists induce mechanical hyperalgesia in the rat. Eur. J. Neurosci. 27, 1700–1709 (2008).

    Article  PubMed  Google Scholar 

  98. Lu, C. L. et al. Estrogen rapidly modulates 5-hydroxytrytophan-induced visceral hypersensitivity via GPR30 in rats. Gastroenterology 137, 1040–1050 (2009).

    Article  CAS  PubMed  Google Scholar 

  99. Hammond, R. & Gibbs, R. B. GPR30 is positioned to mediate estrogen effects on basal forebrain cholinergic neurons and cognitive performance. Brain Res. 16, 53–60 (2011).

    Article  CAS  Google Scholar 

  100. Hammond, R., Nelson, D. & Gibbs, R. B. GPR30 co-localizes with cholinergic neurons in the basal forebrain and enhances potassium-stimulated acetylcholine release in the hippocampus. Psychoneuroendocrinology 36, 182–192 (2011).

    Article  CAS  PubMed  Google Scholar 

  101. Bryant, D. N. & Dorsa, D. M. Roles of estrogen receptors α and β in sexually dimorphic neuroprotection against glutamate toxicity. Neuroscience 170, 1261–1269 (2010).

    Article  CAS  PubMed  Google Scholar 

  102. Lebesgue, D. et al. Acute administration of non-classical estrogen receptor agonists attenuates ischemia-induced hippocampal neuron loss in middle-aged female rats. Plos ONE 5, e8642 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Lebesgue, D., Chevaleyre, V., Zukin, R. S. & Etgen, A. M. Estradiol rescues neurons from global ischemia-induced cell death: multiple cellular pathways of neuroprotection. Steroids 74, 555–561 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Etgen, A. M., Jover-Mengual, T. & Suzanne Zukin, R. Neuroprotective actions of estradiol and novel estrogen analogs in ischemia: Translational implications. Front. Neuroendocrinol. 32, 336–352 (2011).

    Article  CAS  PubMed  Google Scholar 

  105. Xu, H. et al. Extra-nuclear estrogen receptor GPR30 regulates serotonin function in rat hypothalamus. Neuroscience 158, 1599–1607 (2009).

    Article  CAS  PubMed  Google Scholar 

  106. Noel, S. D., Keen, K. L., Baumann, D. I., Filardo, E. J. & Terasawa, E. Involvement of G-protein-coupled receptor 30 (GPR30) in rapid action of estrogen in primate LHRH neurons. Mol. Endocrinol. 23, 349–359 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Terasawa, E., Noel, S. D. & Keen, K. L. Rapid action of oestrogen in luteinising hormone-releasing hormone neurones: the role of GPR30. J. Neuroendocrinol. 21, 316–321 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Lebesgue, D., Reyna-Neyra, A., Huang, X. & Etgen, A. M. GPR30 differentially regulates short latency responses of luteinising hormone and prolactin secretion to oestradiol. J. Neuroendocrinol. 21, 743–752 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Wintermantel, T. M. et al. Definition of estrogen receptor pathway critical for estrogen positive feedback to gonadotropin-releasing hormone neurons and fertility. Neuron 52, 271–280 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Pernis, A. B. Estrogen and CD4+ T cells. Curr. Opin. Rheumatol. 19, 414–420 (2007).

    Article  CAS  PubMed  Google Scholar 

  111. Straub, R. H. The complex role of estrogens in inflammation. Endocr. Rev. 28, 521–574 (2007).

    Article  CAS  PubMed  Google Scholar 

  112. Niino, M., Hirotani, M., Fukazawa, T., Kikuchi, S. & Sasaki, H. Estrogens as potential therapeutic agents in multiple sclerosis. Cent. Nerv. Syst. Agents Med. Chem. 9, 87–94 (2009).

    Article  CAS  PubMed  Google Scholar 

  113. Windahl, S. H. et al. The role of the G-protein-coupled receptor GPR30 in the effects of estrogen in ovariectomized mice. Am. J. Physiol. Endocrinol. Metab. 296, E490–E496 (2009).

    Article  CAS  PubMed  Google Scholar 

  114. Engdahl, C. et al. Amelioration of collagen-induced arthritis and immune-associated bone loss through signaling via estrogen receptor α, and not estrogen receptor β or G-protein-coupled receptor 30. Arthritis Rheum. 62, 524–533 (2010).

    CAS  PubMed  Google Scholar 

  115. Yates, M. A., Li, Y., Chlebeck, P. J. & Offner, H. GPR30, but not estrogen receptor α, is crucial in the treatment of experimental autoimmune encephalomyelitis by oral ethinyl estradiol. BMC Immunol. 11, 20 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Brunsing, R. L. & Prossnitz, E. R. Induction of interleukin-10 in the T helper type 17 effector population by the G-protein-coupled estrogen receptor (GPER) agonist G-1. Immunol. doi:10.1111/j.1365-2567.2011.03471.x.

  117. Meyer, M. R., Haas, E. & Barton, M. Gender differences of cardiovascular disease: new perspectives for estrogen receptor signaling. Hypertension 47, 1019–1026 (2006).

    Article  CAS  PubMed  Google Scholar 

  118. Sandberg, K. Mechanisms underlying sex differences in progressive renal disease. Gend. Med. 5, 10–23 (2008).

    Article  PubMed  Google Scholar 

  119. Barton, M. & Meyer, M. R. Postmenopausal hypertension: mechanisms and therapy. Hypertension 54, 11–18 (2009).

    Article  CAS  PubMed  Google Scholar 

  120. Meyer, M. R., Haas, E. & Barton, M. Need for research on estrogen receptor function: importance for postmenopausal hormone therapy and atherosclerosis. Gend. Med. 5 (Suppl. A), S19–S33 (2008).

    Article  PubMed  Google Scholar 

  121. Ullrich, N. D., Krust, A., Collins, P. & MacLeod, K. T. Genomic deletion of estrogen receptors ERα and ERβ does not alter estrogen-mediated inhibition of Ca2+ influx and contraction in murine cardiomyocytes. Am. J. Physiol. Heart Circ. Physiol. 294, H2421–H2427 (2008).

    Article  CAS  PubMed  Google Scholar 

  122. Karas, R. H. et al. Effects of estrogen on the vascular injury response in estrogen receptor α, β (double) knockout mice. Circ. Res. 89, 534–539 (2001).

    Article  CAS  PubMed  Google Scholar 

  123. Villablanca, A. C. et al. 17β-estradiol prevents early-stage atherosclerosis in estrogen receptor α-deficient female mice. J. Cardiovasc. Transl. Res. 2, 289–299 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  124. Patel, V. H. et al. G-protein-coupled estrogen receptor 1 expression in rat and human heart: Protective role during ischaemic stress. Int. J. Mol. Med. 26, 193–199 (2010).

    CAS  PubMed  Google Scholar 

  125. Recchia, A. G. et al. The G-protein-coupled receptor 30 is up-regulated by hypoxia inducible factor-1a (HIF-1a) in breast cancer cells and cardiomyocytes. J. Biol. Chem. 286, 10773–10782 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Delbeck, M. et al. Impaired left-ventricular cardiac function in male GPR30-deficient mice. Mol. Med. Report. 4, 37–40 (2010).

    Google Scholar 

  127. Deschamps, A. M., Murphy, E. & Sun, J. Estrogen receptor activation and cardioprotection in ischemia reperfusion injury. Trends Cardiovasc. Med. 20, 73–78 (2011).

    Article  CAS  Google Scholar 

  128. Buja, L. M. & Weerasinghe, P. Unresolved issues in myocardial reperfusion injury. Cardiovasc. Pathol. 1 9, 29–35 (2010).

    Article  Google Scholar 

  129. Downey, J. M. & Cohen, M. V. Why do we still not have cardioprotective drugs? Circ. J. 73, 1171–1177 (2009).

    Article  PubMed  Google Scholar 

  130. Deschamps, A. M. & Murphy, E. Activation of a novel estrogen receptor, GPER, is cardioprotective in male and female rats. Am. J. Physiol. Heart Circ. Physiol. 297, H1806–H1813 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Bopassa, J. C., Eghbali, M., Toro, L. & Stefani, E. A novel estrogen receptor GPER inhibits mitochondria permeability transition pore opening and protects the heart against ischemia-reperfusion injury. Am. J. Physiol. Heart Circ. Physiol. 298, H16–H23 (2010).

    Article  CAS  PubMed  Google Scholar 

  132. Weil, B. R. et al. Signaling via GPR30 protects the myocardium from ischemia/reperfusion injury. Surgery 148, 436–443 (2010).

    Article  PubMed  Google Scholar 

  133. Zhang, B. et al. Estradiol and G-1 reduce infarct size and improve immunosuppression after experimental stroke. J. Immunol. 184, 4087–4094 (2010).

    Article  CAS  PubMed  Google Scholar 

  134. Filice, E. et al. A new membrane G-protein-coupled receptor (GPR30) is involved in the cardiac effects of 17β-estradiol in the male rat. J. Physiol. Pharmacol. 60, 3–10 (2009).

    CAS  PubMed  Google Scholar 

  135. Holm, A., Baldetorp, B., Olde, B., Leeb-Lundberg, L. M. & Nilsson, B. O. The GPER1 agonist G-1 attenuates endothelial cell proliferation by inhibiting DNA synthesis and accumulating cells in the S and G2 phases of the cell cycle. J. Vasc. Res. 48, 327–335 (2011).

    Article  CAS  PubMed  Google Scholar 

  136. Haas, E. et al. Differential effects of 17β-estradiol on function and expression of estrogen receptor α, estrogen receptor β, and GPR30 in arteries and veins of patients with atherosclerosis. Hypertension 49, 1358–1363 (2007).

    Article  CAS  PubMed  Google Scholar 

  137. Rettew, J. A., McCall, S. H. T. & Marriott, I. GPR30/GPER1 mediates rapid decreases in TLR4 expression on murine macrophages. Mol. Cell. Endocrinol. 328, 87–92 (2010).

    Article  CAS  PubMed  Google Scholar 

  138. Morales, D. E. et al. Estrogen promotes angiogenic activity in human umbilical vein endothelial cells in vitro and in a murine model. Circulation 91, 755–763 (1995).

    Article  CAS  PubMed  Google Scholar 

  139. Ding, Q., Gros, R., Limbird, L. E., Chorazyczewski, J. & Feldman, R. D. Estradiol-mediated ERK phosphorylation and apoptosis in vascular smooth muscle cells requires GPR30. Am. J. Physiol. Cell Physiol. 297, C1178–C1187 (2009).

    Article  CAS  PubMed  Google Scholar 

  140. Takahashi, K. et al. Both estrogen and raloxifene cause G1 arrest of vascular smooth muscle cells. J. Endocrinol. 178, 319–329 (2003).

    Article  CAS  PubMed  Google Scholar 

  141. Pare, G. et al. Estrogen receptor α mediates the protective effects of estrogen against vascular injury. Circ. Res. 90, 1087–1092 (2002).

    Article  CAS  PubMed  Google Scholar 

  142. Meyer, M. R., Baretella, O., Prossnitz, E. R. & Barton, M. Dilation of epicardial coronary arteries by the G-protein-coupled estrogen receptor agonists G-1 and ICI 182, 780. Pharmacology 86, 58–64 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Broughton, B. R., Miller, A. A. & Sobey, C. G. Endothelium-dependent relaxation by G-protein-coupled receptor 30 agonists in rat carotid arteries. Am. J. Physiol. Heart Circ. Physiol. 298, H1055–H1061 (2010).

    Article  CAS  PubMed  Google Scholar 

  144. Mishra, S. K. et al. Endothelium-dependent relaxation of rat aorta and main pulmonary artery by the phytoestrogens genistein and daidzein. Cardiovasc. Res. 46, 539–546 (2000).

    Article  CAS  PubMed  Google Scholar 

  145. Jessup, J. A., Lindsey, S. H., Wang, H., Chappell, M. C. & Groban, L. Attenuation of salt-induced cardiac remodeling and diastolic dysfunction by the GPER agonist G-1 in female mRen2.Lewis rats. Plos ONE 5, e15433 (2011).

    Article  CAS  Google Scholar 

  146. Lindsey, S. H., Cohen, J. A., Brosnihan, K. B., Gallagher, P. E. & Chappell, M. C. Chronic treatment with the G-protein-coupled receptor 30 agonist G-1 decreases blood pressure in ovariectomized mRen2.Lewis rats. Endocrinology 15 0, 3753–3758 (2009).

    Article  CAS  Google Scholar 

  147. Lindsey, S. H. & Chappell, M. C. GPR30 activation in salt-sensitive mRen2.Lewis females induces beneficial effects independent of alterations in blood pressure FASEB J. (Meeting Abstract Supplement) 1017.18 (2009).

  148. Vanhoutte, P. M., Shimokawa, H., Tang, E. H. & Feletou, M. Endothelial dysfunction and vascular disease. Acta Physiol. (Oxf.) 196, 193–222 (2009).

    Article  CAS  Google Scholar 

  149. Lafferty, A. R. et al. A novel genetic locus for low renin hypertension: familial hyperaldosteronism type II maps to chromosome 7 (7p22). J. Med. Genet. 37, 831–835 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Gilliam-Davis, S., Cohen, J. A., Lindsey, S. H., Yamaleyeva, L. & Chappell, M. C. The estrogen receptor GPR30 is renoprotective in diabetic hypertensive female rats. Hypertension 56, e50–e166 (2010).

    Google Scholar 

  151. Meyer, M. R., Clegg, D. J., Prossnitz, E. R. & Barton, M. Obesity, insulin resistance and diabetes: sex differences and role of oestrogen receptors. Acta Physiol. (Oxf.) doi:10.1111/j.1748-1716.2010.02237.x.

  152. Meyer, M. R. & Barton, M. ERα, ERβ, and GPER: Novel aspects of estrogen receptor signaling in atherosclerosis. Cardiovasc. Res. 83, 605–610 (2009).

    Article  CAS  PubMed  Google Scholar 

  153. Mendelsohn, M. E. & Karas, R. H. Molecular and cellular basis of cardiovascular gender differences. Science 308, 1583–1587 (2005).

    Article  CAS  PubMed  Google Scholar 

  154. Wu, Q., Chambliss, K., Umetani, M., Mineo, C. & Shaul, P. W. Non-nuclear estrogen receptor signaling in endothelium. J. Biol. Chem. 286, 14737–14743 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Faulds, M. H., Zhao, C., Dahlman-Wright, K. & Gustafsson, J. A. Regulation of metabolism by estrogen signaling. J. Endocrinol. doi:10.1530/JOE-11-0044.

  156. Chambliss, K. L. et al. Non-nuclear estrogen receptor a signaling promotes cardiovascular protection but not uterine or breast cancer growth in mice. J. Clin. Invest. 120, 2319–2330 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Nadal, A., Alonso-Magdalena, P., Soriano, S., Ropero, A. B. & Quesada, I. The role of oestrogens in the adaptation of islets to insulin resistance. J. Physiol. 587, 5031–5037 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Nadal, A. et al. Rapid insulinotropic effect of 17β-estradiol via a plasma membrane receptor. FASEB J. 12, 1341–1348 (1998).

    Article  CAS  PubMed  Google Scholar 

  159. Ropero, A. B., Soria, B. & Nadal, A. A nonclassical estrogen membrane receptor triggers rapid differential actions in the endocrine pancreas. Mol. Endocrinol. 16, 497–505 (2002).

    Article  CAS  PubMed  Google Scholar 

  160. Ford, J. et al. GPR30 deficiency causes increased bone mass, mineralization, and growth plate proliferative activity in male mice. J. Bone Miner. Res. 26, 298–307 (2011).

    Article  CAS  PubMed  Google Scholar 

  161. Balhuizen, A., Kumar, R., Amisten, S., Lundquist, I. & Salehi, A. Activation of G-protein-coupled receptor 30 modulates hormone secretion and counteracts cytokine-induced apoptosis in pancreatic islets of female mice. Mol. Cell. Endocrinol. 320, 16–24 (2010).

    Article  CAS  PubMed  Google Scholar 

  162. Shoelson, S. E., Lee, J. & Goldfine, A. B. Inflammation and insulin resistance. J. Clin. Invest. 116, 1793–1801 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Liu, S. & Mauvais-Jarvis, F. Rapid, nongenomic estrogen actions protect pancreatic islet survival. Islets 1, 273–275 (2009).

    Article  PubMed  Google Scholar 

  164. Liu, S. & Mauvais-Jarvis, F. Minireview: Estrogenic protection of β-cell failure in metabolic diseases. Endocrinology 1 51, 859–864 (2010).

    Article  CAS  Google Scholar 

  165. Fu, Z. et al. Genistein induces pancreatic β-cell proliferation through activation of multiple signaling pathways and prevents insulin-deficient diabetes in mice. Endocrinology 151, 3026–3037 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Hugo, E. R. et al. Bisphenol A at environmentally relevant doses inhibits adiponectin release from human adipose tissue explants and adipocytes. Environ. Health Perspect. 116, 1642–1647 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Sharma, G. & Prossnitz, E. R. Mechanisms of estrogen-induced insulin secretion by the G-protein-coupled estrogen receptor GPR30/GPER in pancreatic β cells. Endocrinology 152, 3030–3039 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Kumar, R., Balhuizen, A., Amisten, S., Lundquist, I. & Salehi, A. Insulinotropic and antidiabetic effects of 17β-estradiol and the GPR30 agonist G-1 on human pancreatic islets. Endocrinology 152, 2568–2579 (2011).

    Article  CAS  PubMed  Google Scholar 

  169. Pollanen, E. et al. Differential influence of peripheral and systemic sex steroids on skeletal muscle quality in pre- and postmenopausal women. Aging Cell 10, 650–660 (2011).

    Article  CAS  PubMed  Google Scholar 

  170. Weise, M. et al. Effects of estrogen on growth plate senescence and epiphyseal fusion. Proc. Natl Acad. Sci. USA 98, 6871–6876 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Ohlsson, C. & Vandenput, L. The role of estrogens for male bone health. Eur. J. Endocrinol. 160, 883–889 (2009).

    Article  CAS  PubMed  Google Scholar 

  172. Khosla, S. Update on estrogens and the skeleton. J. Clin. Endocrinol. Metab. 95, 3569–3577 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Carani, C. et al. Effect of testosterone and estradiol in a man with aromatase deficiency. N. Engl. J. Med. 337, 91–95 (1997).

    Article  CAS  PubMed  Google Scholar 

  174. Smith, E. P. et al. Impact on bone of an estrogen receptor a gene loss of function mutation. J. Clin. Endocrinol. Metab. 93, 3088–3096 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Smith, E. P. et al. Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man. N. Engl. J. Med. 331, 1056–1061 (1994).

    Article  CAS  PubMed  Google Scholar 

  176. Chagin, A. S. & Savendahl, L. GPR30 estrogen receptor expression in the growth plate declines as puberty progresses. J. Clin. Endocrinol. Metab. 9 2, 4873–4877 (2007).

    Article  CAS  Google Scholar 

  177. Heino, T. J., Chagin, A. S. & Savendahl, L. The novel estrogen receptor G-protein-coupled receptor 30 is expressed in human bone. J. Endocrinol. 197, R1–R6 (2008).

    Article  CAS  PubMed  Google Scholar 

  178. Jenei-Lanzl, Z. et al. Estradiol inhibits chondrogenic differentiation of mesenchymal stem cells via nonclassic signaling. Arthritis Rheum. 62, 1088–1096 (2010).

    Article  CAS  PubMed  Google Scholar 

  179. Cordera, F. & Jordan, V. C. Steroid receptors and their role in the biology and control of breast cancer growth. Semin. Oncol. 33, 631–641 (2006).

    Article  CAS  PubMed  Google Scholar 

  180. Sengupta, S. & Jordan, V. C. Selective estrogen modulators as an anticancer tool: mechanisms of efficiency and resistance. Adv. Exp. Med. Biol. 630, 206–219 (2008).

    Article  CAS  PubMed  Google Scholar 

  181. Jordan, C. V. et al. Exploiting the apoptotic actions of oestrogen to reverse antihormonal drug resistance in oestrogen receptor positive breast cancer patients. Breast 16 (Suppl. 2), S105–S113 (2007).

    Article  Google Scholar 

  182. Ignatov, A., Ignatov, T., Roessner, A., Costa, S. D. & Kalinski, T. Role of GPR30 in the mechanisms of tamoxifen resistance in breast cancer MCF-7 cells. Breast Cancer Res. Treat. 123, 87–96 (2010).

    Article  CAS  PubMed  Google Scholar 

  183. Filardo, E. J. et al. 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, 6359–6366 (2006).

    Article  CAS  PubMed  Google Scholar 

  184. Tu, G., Hu, D., Yang, G. & Yu, T. The correlation between GPR30 and clinicopathologic variables in breast carcinomas. Technol. Cancer Res. Treat 8, 231–234 (2009).

    Article  CAS  PubMed  Google Scholar 

  185. Liu, Q., Li, J. G., Zheng, X. Y., Jin, F. & Dong, H. T. Expression of CD133, PAX2, ESA, and GPR30 in invasive ductal breast carcinomas. Chin. Med. J. 122, 2763–2769 (2009).

    PubMed  Google Scholar 

  186. Ignatov, A. et al. G-protein-coupled estrogen receptor GPR30 and tamoxifen resistance in breast cancer. Breast Cancer Res. Treat. 128, 457–466 (2011).

    Article  CAS  PubMed  Google Scholar 

  187. Albanito, L. et al. Epidermal growth factor induces G-protein-coupled receptor 30 expression in estrogen receptor-negative breast cancer cells. Endocrinology 149, 3799–3808 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. He, Y. Y., Cai, B., Yang, Y. X., Liu, X. L. & Wan, X. P. Estrogenic G-protein-coupled receptor 30 signaling is involved in regulation of endometrial carcinoma by promoting proliferation, invasion potential, and interleukin-6 secretion via the MEK/ERK mitogen-activated protein kinase pathway. Cancer Sci. 100, 1051–1061 (2009).

    Article  CAS  PubMed  Google Scholar 

  189. Leblanc, K. et al. Effects of 4-hydroxytamoxifen, raloxifene and ICI 182 780 on survival of uterine cancer cell lines in the presence and absence of exogenous estrogens. Int. J. Oncol. 30, 477–487 (2007).

    CAS  PubMed  Google Scholar 

  190. Vivacqua, A. et al. 17β-estradiol, genistein and 4-hydroxytamoxifen induce the proliferation of thyroid cancer cells through the G-protein-coupled receptor GPR30. Mol. Pharmacol. 70, 1414–1423 (2006).

    Article  CAS  PubMed  Google Scholar 

  191. Henic, E., Noskova, V., Hoyer-Hansen, G., Hansson, S. & Casslen, B. Estradiol attenuates EGF-induced rapid uPAR mobilization and cell migration via the G-protein-coupled receptor 30 in ovarian cancer cells. Int. J. Gynecol. Cancer 19, 214–222 (2009).

    Article  PubMed  Google Scholar 

  192. Siegfried, J. M., Hershberger, P. A. & Stabile, L. P. Estrogen receptor signaling in lung cancer. Seminars in Oncology 36, 524–531 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Chan, Q. K. et al. Activation of GPR30 inhibits the growth of prostate cancer cells through sustained activation of Erk1/2, c-jun/c-fos-dependent upregulation of p21, and induction of G2 cell-cycle arrest. Cell Death Differ. 17, 1511–1523 (2010).

    Article  CAS  PubMed  Google Scholar 

  194. Franco, R. et al. GPR30 is over-expressed in post puberal testicular germ cell tumors. Cancer Biol. Ther. 11, 609–613 (2011).

    Article  CAS  PubMed  Google Scholar 

  195. Vivacqua, A. et al. The G-protein-coupled receptor GPR30 mediates the proliferative effects induced by 17β-estradiol and hydroxytamoxifen in endometrial cancer cells. Mol. Endocrinol. 20, 631–646 (2006).

    Article  CAS  PubMed  Google Scholar 

  196. Dong, S., Terasaka, S. & Kiyama, R. Bisphenol A induces a rapid activation of Erk1/2 through GPR30 in human breast cancer cells. Environ. Pollut. 159, 212–218 (2011).

    Article  CAS  PubMed  Google Scholar 

  197. Lucki, N. C. & Sewer, M. B. Genistein stimulates MCF-7 breast cancer cell growth by inducing acid ceramidase (ASAH1) gene expression. J. Biol. Chem. 286, 19399–19409 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Smith, H. O. et al. GPR30: a novel indicator of poor survival for endometrial carcinoma. Am. J. Obstet. Gynecol. 196, 386.e1–e11 (2007).

    Article  CAS  Google Scholar 

  199. Smith, H. O. et al. GPR30 predicts poor survival for ovarian cancer. Gynecol. Oncol. 114, 465–471 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Pandey, D. P. et al. Estrogenic GPR30 signalling induces proliferation and migration of breast cancer cells through CTGF. EMBO J. 28, 523–532 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Ignatov, T. et al. Role of GPR30 in endometrial pathology after tamoxifen for breast cancer. Am. J. Obstet. Gynecol. 203, 595 e9–e16 (2011).

    Article  CAS  Google Scholar 

  202. van Leeuwen, F. E. et al. Risk of endometrial cancer after tamoxifen treatment of breast cancer. Lancet 343, 448–452 (1994).

    Article  CAS  PubMed  Google Scholar 

  203. Madeo, A. & Maggiolini, M. Nuclear alternate estrogen receptor GPR30 mediates 17β-estradiol-induced gene expression and migration in breast cancer-associated fibroblasts. Cancer Res. 7 0, 6036–6046 (2010).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

E. R. Prossnitzis supported by grants CA116662, CA118743 and CA127731 from the NIH. M. Barton is supported by grants 3,200-108,528/1 and K-33KO-122,504/1 from the Swiss National Science Foundation (SNSF).

Author information

Authors and Affiliations

  1. Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, 87131, NM, USA

    Eric R. Prossnitz

  2. Molecular Internal Medicine, University of Zürich, LTK Y44 G22, Winterthurerstrasse 190, 8057, Zürich, Switzerland

    Matthias Barton

Authors
  1. Eric R. Prossnitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Matthias Barton
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Both authors contributed equally to all aspects of this manuscript.

Corresponding author

Correspondence to Eric R. Prossnitz.

Ethics declarations

Competing interests

E. R. Prossnitz declares that he is an inventor on US Patent number 7,875,721: Compounds for binding to ERα/β and GPR30, methods of treating disease states and conditions mediated through these receptors and identification thereof. M. Barton declares no competing interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Prossnitz, E., Barton, M. The G-protein-coupled estrogen receptor GPER in health and disease. Nat Rev Endocrinol 7, 715–726 (2011). https://doi.org/10.1038/nrendo.2011.122

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrendo.2011.122

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing