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Science 307 (5715): 1625-1630

Copyright © 2005 by the American Association for the Advancement of Science

A Transmembrane Intracellular Estrogen Receptor Mediates Rapid Cell Signaling

Chetana M. Revankar,1,2 Daniel F. Cimino,1,2 Larry A. Sklar,2,3 Jeffrey B. Arterburn,4 Eric R. Prossnitz1,2*

Abstract: The steroid hormone estrogen regulates many functionally unrelated processes in numerous tissues. Although it is traditionally thought to control transcriptional activation through the classical nuclear estrogen receptors, it also initiates many rapid nongenomic signaling events. We found that of all G protein–coupled receptors characterized to date, GPR30 is uniquely localized to the endoplasmic reticulum, where it specifically binds estrogen and fluorescent estrogen derivatives. Activating GPR30 by estrogen resulted in intracellular calcium mobilization and synthesis of phosphatidylinositol 3,4,5-trisphosphate in the nucleus. Thus, GPR30 represents an intracellular transmembrane estrogen receptor that may contribute to normal estrogen physiology as well as pathophysiology.

1 Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
2 Cancer Research and Treatment Center, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
3 Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
4 Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, NM 88003, USA.

* To whom correspondence should be addressed. E-mail: eprossnitz{at}

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Estradiol-mediated ERK phosphorylation and apoptosis in vascular smooth muscle cells requires GPR 30.
Q. Ding, R. Gros, L. E. Limbird, J. Chorazyczewski, and R. D. Feldman (2009)
Am J Physiol Cell Physiol 297, C1178-C1187
   Abstract »    Full Text »    PDF »
Activation of a novel estrogen receptor, GPER, is cardioprotective in male and female rats.
A. M. Deschamps and E. Murphy (2009)
Am J Physiol Heart Circ Physiol 297, H1806-H1813
   Abstract »    Full Text »    PDF »
Membrane oestrogen receptor signalling to cell functions.
E. R. Levin (2009)
J. Physiol. 587, 5019-5023
   Abstract »    Full Text »    PDF »
The role of oestrogens in the adaptation of islets to insulin resistance.
A. Nadal, P. Alonso-Magdalena, S. Soriano, A. B. Ropero, and I. Quesada (2009)
J. Physiol. 587, 5031-5037
   Abstract »    Full Text »    PDF »
Importance of Extranuclear Estrogen Receptor-{alpha} and Membrane G Protein-Coupled Estrogen Receptor in Pancreatic Islet Survival.
S. Liu, C. Le May, W. P.S. Wong, R. D. Ward, D. J. Clegg, M. Marcelli, K. S. Korach, and F. Mauvais-Jarvis (2009)
Diabetes 58, 2292-2302
   Abstract »    Full Text »    PDF »
Functional requirement of AgRP and NPY neurons in ovarian cycle-dependent regulation of food intake.
L. E. Olofsson, A. A. Pierce, and A. W. Xu (2009)
PNAS 106, 15932-15937
   Abstract »    Full Text »    PDF »
Estrogen can signal through multiple pathways to regulate oocyte cyst breakdown and primordial follicle assembly in the neonatal mouse ovary.
Y. Chen, K. Breen, and M. E Pepling (2009)
J. Endocrinol. 202, 407-417
   Abstract »    Full Text »    PDF »
ER{alpha}, ER{beta}, and gpER: novel aspects of oestrogen receptor signalling in atherosclerosis.
M. R. Meyer and M. Barton (2009)
Cardiovasc Res 83, 605-610
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Localisation of GPR30, a novel G protein-coupled oestrogen receptor, suggests multiple functions in rodent brain and peripheral tissues.
G. G J Hazell, S. T Yao, J. A Roper, E. R Prossnitz, A.-M. O'Carroll, and S. J Lolait (2009)
J. Endocrinol. 202, 223-236
   Abstract »    Full Text »    PDF »
Intracellular activation of vasopressin V2 receptor mutants in nephrogenic diabetes insipidus by nonpeptide agonists.
J. H. Robben, M. L. A. Kortenoeven, M. Sze, C. Yae, G. Milligan, V. M. Oorschot, J. Klumperman, N. V. A. M. Knoers, and P. M. T. Deen (2009)
PNAS 106, 12195-12200
   Abstract »    Full Text »    PDF »
Role of the Oestrogen Receptors GPR30 and ER{alpha} in Peripheral Sensitization: Relevance to Trigeminal Pain Disorders in Women.
C. Liverman, J. Brown, R Sandhir, K. McCarson, and N. Berman (2009)
Cephalalgia 29, 729-741
   Abstract »    Full Text »    PDF »
17{beta}-Estradiol inhibits 11{beta}-hydroxysteroid dehydrogenase type 1 activity in rodent adipocytes.
N. Tagawa, R. Yuda, S. Kubota, M. Wakabayashi, Y. Yamaguchi, D. Kiyonaga, N. Mori, E. Minamitani, H. Masuzaki, and Y. Kobayashi (2009)
J. Endocrinol. 202, 131-139
   Abstract »    Full Text »    PDF »

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