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

Nature Reviews Endocrinology

Volumn 7, Issue 12, 2011, Pages 715-726

  Prossnitz, Eric R ^a   Barton, Matthias ^b  

^a UNIVERSITY OF NEW MEXICO HEALTH SCIENCES CENTER   (United States)

^b UNIVERSITY OF ZURICH   (Switzerland)

Author keywords

[No Author keywords available]

Indexed keywords

4,4' ISOPROPYLIDENEDIPHENOL; ANTIESTROGEN; COUMESTROL; DIETHYLSTILBESTROL; ESTRADIOL; ESTROGEN; ESTROGEN RECEPTOR; ESTROGEN RECEPTOR ALPHA; ESTROGEN RECEPTOR BETA; ESTRONE; FULVESTRANT; G PROTEIN COUPLED RECEPTOR; G PROTEIN COUPLED RECEPTOR 30; GENISTEIN; LIGAND; RALOXIFENE; SELECTIVE ESTROGEN RECEPTOR MODULATOR; TAMOXIFEN;

BONE GROWTH; CANCER GROWTH; CARDIOVASCULAR SYSTEM; CARTILAGE CELL; GENERAL ASPECTS OF DISEASE; GLUCOSE METABOLISM; HUMAN; METASTASIS; NEUROENDOCRINOLOGY; PANCREAS FUNCTION; PATHOPHYSIOLOGY; PHYSIOLOGICAL PROCESS; PREMENOPAUSE; PRIORITY JOURNAL; PROGNOSIS; PROTEIN EXPRESSION; RENAL SYSTEM PARAMETERS; REVIEW; SIGNAL TRANSDUCTION;

ANIMALS; CARDIOVASCULAR SYSTEM; ENDOCRINE SYSTEM; ESTRADIOL; FEMALE; GENISTEIN; HUMANS; IMMUNE SYSTEM; MALE; NEOPLASMS; NERVOUS SYSTEM; PHENOLS; PREMENOPAUSE; RECEPTORS, ESTROGEN; RECEPTORS, G-PROTEIN-COUPLED; SIGNAL TRANSDUCTION;

EID: 82155173499     PISSN: 17595029     EISSN: 17595037     Source Type: Journal    
DOI: 10.1038/nrendo.2011.122     Document Type: Review

References (203)

1. Hess, R. A. Estrogen in the adult male reproductive tract: a review. Reprod. Biol. Endocrinol. 1, 52 (2003).
2. Deroo, B. J. & Korach, K. S. Estrogen receptors and human disease. J. Clin. Invest. 116, 561-570 (2006).
3. Prossnitz, E. R. et al. Estrogen signaling through the transmembrane G-protein-coupled receptor GPR30. Annu. Rev. Physiol. 70, 165-190 (2008).
4. Edwards, D. P. Regulation of signal transduction pathways by estrogen and progesterone. Annu. Rev. Physiol. 67, 335-376 (2005).
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).
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).
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).
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).
9. Carroll, J. S. & Brown, M. Estrogen receptor target gene: an evolving concept. Mol. Endocrinol. 20, 1707-1714 (2006).
10. Hewitt, S. C. & Korach, K. S. Oestrogen receptor knockout mice: roles for oestrogen receptors α and β in reproductive tissues. Reproduction 125, 143-149 (2003).
11. Hammes, S. R. & Levin, E. R. Extranuclear steroid receptors: nature and actions. Endocr. Rev. 28, 726-741 (2007).
12. Pietras, R. J. & Szego, C. M. Endometrial cell calcium and oestrogen action. Nature 253, 357-359 (1975).
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).
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).
15. Wehling, M. Looking beyond the dogma of genomic steroid action: insights and facts of the 1990s. J. Mol. Med. 73, 439-447 (1995).
16. Wehling, M. Specific, nongenomic actions of steroid hormones. Annu. Rev. Physiol. 59, 365-393 (1997).
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).
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).
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).
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).
21. O'Dowd, B. F. et al. Discovery of three novel G-protein-coupled receptor genes. Genomics 47, 310-313 (1998).
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).
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. 240, 737-741 (1997).
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).
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).
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. 121, 771-780 (2003).
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).
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).
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).
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).
31. Ahola, T. M. et al. Progestin upregulates G-protein-coupled receptor 30 in breast cancer cells. Eur. J. Biochem. 269, 2485-2490 (2002).
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).
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 307, 1625-1630 (2005).
34. Olde, B. & Leeb-Lundberg, L. M. GPR30/GPER1: searching for a role in estrogen physiology. Trends Endocrinol. Metab. 20, 409-416 (2009).
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).
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).
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).
38. Geisler, J. Breast cancer tissue estrogens and their manipulation with aromatase inhibitors and inactivators. J. Steroid Biochem. Mol. Biol. 86, 245-253 (2003).
39. Diczfalusky, E. & Mancuso, S. in Foetus and Placenta (eds. Klopper, A. & Diczfalusky, E) (Blackwell, Oxford, 1969).
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. 117, 401-421 (1979).
41. Ososki, A. L. & Kennelly, E. J. Phytoestrogens: a review of the present state of research. Phytother. Res. 17, 845-869 (2003).
42. Starek, A. Estrogens and organochlorine xenoestrogens and breast cancer risk. Int. J. Occup. Med. Environ. Health 16, 113-124 (2003).
43. Singleton, D. W. & Khan, S. A. Xenoestrogen exposure and mechanisms of endocrine disruption. Front. Biosci. 8, s110-s118 (2003).
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).
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).
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).
48. Setchell, K. D. & Clerici, C. Equol: history, chemistry, and formation. J. Nutr. 140, 1355S-1362S (2010).
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).
50. Jordan, V. C. SERMs: meeting the promise of multifunctional medicines. J. Natl Cancer Inst. 99, 350-356 (2007).
51. Orlando, L. et al. Molecularly targeted endocrine therapies for breast cancer. Cancer Treat. Rev. 36 (Suppl. 3), S67-S71 (2011).
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).
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).
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).
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).
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).
58. Haas, E. et al. Regulatory role of G-protein-coupled estrogen receptor for vascular function and obesity. Circ. Res. 104, 288-291 (2009).
59. Dennis, M. K. et al. In vivo effects of a GPR30 antagonist. Nat. Chem. Biol. 5, 421-427 (2009).
60. Jenei-Lanzl, Z. et al. Estradiol inhibits chondrogenic differentiation of mesenchymal stem cells via nonclassic signaling. Arthritis Rheum. 62, 1088-1096 (2011).
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).
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).
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).
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).
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).
66. Levin, E. R. Minireview: extranuclear steroid receptors: roles in modulation of cell functions. Mol. Endocrinol. 25, 377-384 (2011).
67. Otto, C. et al. GPR30 localizes to the endoplasmic reticulum and is not activated by estradiol. Endocrinology 149, 4846-4856 (2008).
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).
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).
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).
71. Prenzel, N. et al. EGF receptor transactivation by G-protein-coupled receptors requires metalloproteinase cleavage of proHB-EGF. Nature 402, 884-888 (1999).
72. Edwin, F. et al. A historical perspective of the EGF receptor and related systems. Methods Mol. Biol. 327, 1-24 (2006).
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).
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).
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).
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).
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).
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).
79. Maggiolini, M. & Picard, D. The unfolding stories of GPR30, a new membrane-bound estrogen receptor. J. Endocrinol. 204, 105-114 (2010).
80. Prossnitz, E. R. & Maggiolini, M. Mechanisms of estrogen signaling and gene expression via GPR30. Mol. Cell Endocrinol. 308, 32-38 (2009).
81. Isensee, J. et al. Expression pattern of G-protein-coupled receptor 30 in LacZ reporter mice. Endocrinology 150, 1722-1730 (2009).
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).
83. Otto, C. et al. GPR30 does not mediate estrogenic responses in reproductive organs in mice. Biol. Reprod. 80, 34-41 (2009).
84. Wang, C. et al. GPR30 contributes to estrogen-induced thymic atrophy. Mol. Endocrinol. 22, 636-648 (2008).
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).
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 152, 1434-1447 (2011).
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).
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).
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).
90. Maiti, K. et al. G-1-activated membrane estrogen receptors mediate increased contractility of the human myometrium. Endocrinology 152, 2448-2455 (2011).
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).
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).
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).
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).
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).
97. Kuhn, J. et al. GPR30 estrogen receptor agonists induce mechanical hyperalgesia in the rat. Eur. J. Neurosci. 27, 1700-1709 (2008).
98. Lu, C. L. et al. Estrogen rapidly modulates 5-hydroxytrytophan-induced visceral hypersensitivity via GPR30 in rats. Gastroenterology 137, 1040-1050 (2009).
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).
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).
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).
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).
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).
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).
105. Xu, H. et al. Extra-nuclear estrogen receptor GPR30 regulates serotonin function in rat hypothalamus. Neuroscience 158, 1599-1607 (2009).
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).
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).
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).
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).
110. 4+ T cells. Curr. Opin. Rheumatol. 19, 414-420 (2007).
111. Straub, R. H. The complex role of estrogens in inflammation. Endocr. Rev. 28, 521-574 (2007).
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).
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).
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).
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).
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).
118. Sandberg, K. Mechanisms underlying sex differences in progressive renal disease. Gend. Med. 5, 10-23 (2008).
119. Barton, M. & Meyer, M. R. Postmenopausal hypertension: mechanisms and therapy. Hypertension 54, 11-18 (2009).
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).
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).
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).
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).
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).
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).
126. Delbeck, M. et al. Impaired left-ventricular cardiac function in male GPR30-deficient mice. Mol. Med. Report. 4, 37-40 (2010).
127. Deschamps, A. M., Murphy, E. & Sun, J. Estrogen receptor activation and cardioprotection in ischemia reperfusion injury. Trends Cardiovasc. Med. 20, 73-78 (2011).
128. Buja, L. M. & Weerasinghe, P. Unresolved issues in myocardial reperfusion injury. Cardiovasc. Pathol. 19, 29-35 (2010).
129. Downey, J. M. & Cohen, M. V. Why do we still not have cardioprotective drugs? Circ. J. 73, 1171-1177 (2009).
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).
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).
132. Weil, B. R. et al. Signaling via GPR30 protects the myocardium from ischemia/reperfusion injury. Surgery 148, 436-443 (2010).
133. Zhang, B. et al. Estradiol and G-1 reduce infarct size and improve immunosuppression after experimental stroke. J. Immunol. 184, 4087-4094 (2010).
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).
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).
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).
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).
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).
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).
140. Takahashi, K. et al. Both estrogen and raloxifene cause G1 arrest of vascular smooth muscle cells. J. Endocrinol. 178, 319-329 (2003).
141. Pare, G. et al. Estrogen receptor α mediates the protective effects of estrogen against vascular injury. Circ. Res. 90, 1087-1092 (2002).
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).
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).
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).
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).
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 150, 3753-3758 (2009).
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).
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).
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).
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).
153. Mendelsohn, M. E. & Karas, R. H. Molecular and cellular basis of cardiovascular gender differences. Science 308, 1583-1587 (2005).
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).
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).
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).
158. Nadal, A. et al. Rapid insulinotropic effect of 17β-estradiol via a plasma membrane receptor. FASEB J. 12, 1341-1348 (1998).
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).
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).
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).
162. Shoelson, S. E., Lee, J. & Goldfine, A. B. Inflammation and insulin resistance. J. Clin. Invest. 116, 1793-1801 (2006).
163. Liu, S. & Mauvais-Jarvis, F. Rapid, nongenomic estrogen actions protect pancreatic islet survival. Islets 1, 273-275 (2009).
164. Liu, S. & Mauvais-Jarvis, F. Minireview: Estrogenic protection of β-cell failure in metabolic diseases. Endocrinology 151, 859-864 (2010).
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).
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).
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).
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).
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).
170. Weise, M. et al. Effects of estrogen on growth plate senescence and epiphyseal fusion. Proc. Natl Acad. Sci. USA 98, 6871-6876 (2001).
171. Ohlsson, C. & Vandenput, L. The role of estrogens for male bone health. Eur. J. Endocrinol. 160, 883-889 (2009).
172. Khosla, S. Update on estrogens and the skeleton. J. Clin. Endocrinol. Metab. 95, 3569-3577 (2010).
173. Carani, C. et al. Effect of testosterone and estradiol in a man with aromatase deficiency. N. Engl. J. Med. 337, 91-95 (1997).
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).
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).
176. Chagin, A. S. & Savendahl, L. GPR30 estrogen receptor expression in the growth plate declines as puberty progresses. J. Clin. Endocrinol. Metab. 92, 4873-4877 (2007).
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).
178. Jenei-Lanzl, Z. et al. Estradiol inhibits chondrogenic differentiation of mesenchymal stem cells via nonclassic signaling. Arthritis Rheum. 62, 1088-1096 (2010).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
192. Siegfried, J. M., Hershberger, P. A. & Stabile, L. P. Estrogen receptor signaling in lung cancer. Seminars in Oncology 36, 524-531 (2009).
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).
194. Franco, R. et al. GPR30 is over-expressed in post puberal testicular germ cell tumors. Cancer Biol. Ther. 11, 609-613 (2011).
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).
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).
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).
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).
199. Smith, H. O. et al. GPR30 predicts poor survival for ovarian cancer. Gynecol. Oncol. 114, 465-471 (2009).
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).
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).
202. van Leeuwen, F. E. et al. Risk of endometrial cancer after tamoxifen treatment of breast cancer. Lancet 343, 448-452 (1994).
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. 70, 6036-6046 (2010).