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This version published online on July 1, 2004
Molecular Endocrinology, doi:10.1210/me.2004-0115
Molecular Endocrinology Vol. 0, No. 2004 200401151-
doi:10.1210/me.2004-0115
Copyright © 2004 by the Endocrine Society.
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Submitted on March 17, 2004
Accepted on June 28, 2004

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, CA. 90822, Departments of Medicine and Pharmacology, and the University of California, Irvine, Irvine CA., 92717, Woman's Health Research Institute, Wyeth Research, Collegeville, PA., 19426, Ben May Institute, University of Chicago, Chicago, IL., 60637

* To whom correspondence should be addressed. E-mail: ellis.levin{at}med.va.gov.

A small pool of estrogen receptors ER{alpha} and {beta} 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 (EC) exist predominantly as homodimers in the presence of 17-{beta}-estradiol. Interestingly, in EC made from ER{alpha} /ER{beta} homozygous double knockout mice, membrane ER{alpha} or ER{beta} 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 CHO cells, we expressed and compared wt and dimer mutant mouse ER{alpha}. Only wildtype ER{alpha} supported the ability of estradiol (E2) to rapidly activate ERK, cAMP, and PI3 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 EGFR 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 ER exist as dimers, a structural requirement that supports rapid signal transduction and affects cell physiology.
Key words: Estrogen receptor • Signaling • G protein • Cell survival

NURSA Molecule Pages Link:

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



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