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Endocrinology, doi:10.1210/en.2004-1064
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Endocrinology Vol. 146, No. 2 624-632
Copyright © 2005 by The Endocrine Society

Identity of an Estrogen Membrane Receptor Coupled to a G Protein in Human Breast Cancer Cells

P. Thomas, Y. Pang, E. J. Filardo and J. Dong

Marine Science Institute (P.T., Y.P., J.D.), University of Texas at Austin, Port Aransas, Texas 78373; and Department of Medicine (E.J.F.), Brown University School of Medicine, Providence, Rhode Island 02903

Address all correspondence and requests for reprints to: Peter Thomas, University of Texas Marine Science Institute, 750 Channel View Drive, Port Aransas, Texas 78373. E-mail: thomas{at}utmsi.utexas.edu.

Although nonclassical estrogen actions initiated at the cell surface have been described in many tissues, the identities of the membrane estrogen receptors (mERs) mediating these actions remain unclear. Here we show that GPR30, an orphan receptor unrelated to nuclear estrogen receptors, has all the binding and signaling characteristics of a mER. A high-affinity (dissociation constant 2.7 nM), limited capacity, displaceable, single binding site specific for estrogens was detected in plasma membranes of SKBR3 breast cancer cells that express GPR30 but lack nuclear estrogen receptors. Progesterone-induced increases and small interfering RNA-induced decreases in GPR30 expression in SKBR3 cells were accompanied by parallel changes in specific estradiol-17ß (E2) binding. Plasma membranes of human embryonic kidney 293 cells transfected with GPR30, but not those of untransfected cells, and human placental tissues that express GPR30 also displayed high-affinity, specific estrogen binding typical of mERs. E2 treatment of transfected cell membranes caused activation of a stimulatory G protein that is directly coupled to the receptor, indicating GPR30 is a G protein-coupled receptor (GPCR), and also increased adenylyl cyclase activity. The finding that the antiestrogens tamoxifen and ICI 182,780, and an environmental estrogen, ortho,para-dichlorodiphenyldichloroethylene (o,p'-DDE), have high binding affinities to the receptor and mimic the actions of E2 has important implications for both the development and treatment of estrogen-dependent breast cancer. GPR30 is structurally unrelated to the recently discovered family of GPCR-like membrane progestin receptors. The identification of a second distinct class of GPCR-like steroid membrane receptors suggests a widespread role for GPCRs in nonclassical steroid hormone actions.




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Am J Physiol Cell Physiol, April 1, 2006; 290(4): C1067 - C1075.
[Abstract] [Full Text] [PDF]

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 Mol. Endocrinol.Home page
A. Vivacqua, D. Bonofiglio, A. G. Recchia, A. M. Musti, D. Picard, S. Ando, and M. Maggiolini
The G Protein-Coupled Receptor GPR30 Mediates the Proliferative Effects Induced by 17{beta}-Estradiol and Hydroxytamoxifen in Endometrial Cancer Cells
Mol. Endocrinol., March 1, 2006; 20(3): 631 - 646.
[Abstract] [Full Text] [PDF]

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 Mol. Endocrinol.Home page
W. R. Harrington, S. H. Kim, C. C. Funk, Z. Madak-Erdogan, R. Schiff, J. A. Katzenellenbogen, and B. S. Katzenellenbogen
Estrogen Dendrimer Conjugates that Preferentially Activate Extranuclear, Nongenomic Versus Genomic Pathways of Estrogen Action
Mol. Endocrinol., March 1, 2006; 20(3): 491 - 502.
[Abstract] [Full Text] [PDF]

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 ReproductionHome page
Y. Wu, W. G Foster, and E. V Younglai
Rapid effects of pesticides on human granulosa-lutein cells
Reproduction, February 1, 2006; 131(2): 299 - 310.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
M. M. Khan, M. Hadman, C. Wakade, L. M. De Sevilla, K. M. Dhandapani, V. B. Mahesh, R. K. Vadlamudi, and D. W. Brann
Cloning, Expression, and Localization of MNAR/PELP1 in Rodent Brain: Colocalization in Estrogen Receptor-{alpha}- But Not in Gonadotropin-Releasing Hormone-Positive Neurons
Endocrinology, December 1, 2005; 146(12): 5215 - 5227.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
M. N. Chernova, D. H. Vandorpe, J. S. Clark, J. I. Williams, M. A. Zasloff, L. Jiang, and S. L. Alper
Apparent receptor-mediated activation of Ca2+-dependent conductive Cl- transport by shark-derived polyaminosterols
Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2005; 289(6): R1644 - R1658.
[Abstract] [Full Text] [PDF]

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 HypertensionHome page
P. J. Fuller and M. J. Young
Mechanisms of Mineralocorticoid Action
Hypertension, December 1, 2005; 46(6): 1227 - 1235.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
T. M. D'Eon, S. C. Souza, M. Aronovitz, M. S. Obin, S. K. Fried, and A. S. Greenberg
Estrogen Regulation of Adiposity and Fuel Partitioning: EVIDENCE OF GENOMIC AND NON-GENOMIC REGULATION OF LIPOGENIC AND OXIDATIVE PATHWAYS
J. Biol. Chem., October 28, 2005; 280(43): 35983 - 35991.
[Abstract] [Full Text] [PDF]

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 Hum ReprodHome page
E.V. Younglai, Y.J. Wu, T.K. Kwan, and C.-Y. Kwan
Non-genomic action of estradiol and progesterone on cytosolic calcium concentrations in primary cultures of human granulosa-lutein cells
Hum. Reprod., September 1, 2005; 20(9): 2383 - 2390.
[Abstract] [Full Text] [PDF]

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 Integr. Comp. Biol.Home page
J. G. Tasker, S. Di, and R. Malcher-Lopes
Rapid Central Corticosteroid Effects: Evidence for Membrane Glucocorticoid Receptors in the Brain
Integr. Comp. Biol., August 1, 2005; 45(4): 665 - 671.
[Abstract] [Full Text] [PDF]

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 Mol. Endocrinol.Home page
E. R. Levin
Integration of the Extranuclear and Nuclear Actions of Estrogen
Mol. Endocrinol., August 1, 2005; 19(8): 1951 - 1959.
[Abstract] [Full Text] [PDF]

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 HypertensionHome page
M. Wehling
Rapid Effects of Aldosterone: Relevant in Cardiac Ischemia?
Hypertension, July 1, 2005; 46(1): 27 - 28.
[Full Text] [PDF]

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 Mol. Interv.Home page
A. Hasbi, B. F. O'Dowd, and S. R. George
A G Protein-Coupled Receptor For Estrogen: The End Of The Search?
Mol. Interv., June 1, 2005; 5(3): 158 - 161.
[Abstract] [Full Text] [PDF]

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 J. Physiol.Home page
R. R. Magness, T. M. Phernetton, T. C. Gibson, and D.-b. Chen
Uterine blood flow responses to ICI 182 780 in ovariectomized oestradiol-17{beta}-treated, intact follicular and pregnant sheep
J. Physiol., May 15, 2005; 565(1): 71 - 83.
[Abstract] [Full Text] [PDF]

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 ScienceHome page
C. M. Revankar, D. F. Cimino, L. A. Sklar, J. B. Arterburn, and E. R. Prossnitz
A Transmembrane Intracellular Estrogen Receptor Mediates Rapid Cell Signaling
Science, March 11, 2005; 307(5715): 1625 - 1630.
[Abstract] [Full Text] [PDF]


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