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Molecular Endocrinology, doi:10.1210/me.2004-0115
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Molecular Endocrinology 18 (12): 2854-2865
Copyright © 2004 by The Endocrine Society

Plasma Membrane Estrogen Receptors Exist and Functions as Dimers

Mahnaz Razandi, Ali Pedram, Istvan Merchenthaler, Geoffrey L. Greene and Ellis R. Levin

Division of Endocrinology, Veterans Affairs Medical Center, Long Beach, Long Beach, California 90822; Departments of Medicine (M.R., A.P., E.R.L.) and Pharmacology, and the University of California, Irvine, Irvine, California 92717; Woman’s Health Research Institute (I.M.), Wyeth Research, Collegeville, Pennsylvania 19426; and Ben May Institute (G.L.G.), University of Chicago, Chicago, Illinois 60637

Address all correspondence and requests for reprints to: Ellis R. Levin, M.D., Medical Service (111-I) Long Beach Veterans Affairs Medical Center/University of California-Irvine, 5901 East 7th Street, Long Beach, California 90822. E-mail: ellis.levin{at}med.va.gov.

A small pool of estrogen receptors (ER{alpha} and -ß) localize at the plasma membrane and rapidly signal to affect cellular physiology. Although nuclear ERs function mainly as homodimers, it is unknown whether membrane-localized ER exists or functions with similar requirements. We report that the endogenous ER isoforms at the plasma membrane of breast cancer or endothelial cells exist predominantly as homodimers in the presence of 17ß-estradiol (E2). Interestingly, in endothelial cells made from ER{alpha} /ERß homozygous double-knockout mice, membrane ER{alpha} or ERß are absent, indicating that the endogenous membrane receptors derive from the same gene(s) as the nuclear receptors. In ER-negative breast cancer cells or Chinese hamster ovary cells, we expressed and compared wild-type and dimer mutant mouse ER{alpha}. Only wild-type ER{alpha} supported the ability of E2 to rapidly activate ERK, cAMP, and phosphatidylinositol 3-kinase signaling. This resulted from E2 activating Gs{alpha} and Gq{alpha} at the membrane in cells expressing the wild-type, but not the dimer mutant, ER{alpha}. Intact, but not dimer mutant, ER{alpha} also supported E2-induced epidermal growth factor receptor transactivation and cell survival. We also confirmed the requirement of dimerization for membrane ER function using a second, less extensively mutated, human ER{alpha}. In summary, endogenous membrane ERs exist as dimers, a structural requirement that supports rapid signal transduction and affects cell physiology.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα  |  ERβ
Ligands:   17β-Estradiol



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