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This version published online on April 3, 2007
Molecular Endocrinology, doi:10.1210/me.2006-0360
Molecular Endocrinology Vol. 0, No. 2007 200603601-
doi:10.1210/me.2006-0360
Copyright © 2007 by the Endocrine Society.
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Submitted on August 30, 2006
Accepted on March 28, 2007

Direct Interactions with G{alpha}I and G{beta}{gamma} Mediate Nongenomic Signaling by ER{alpha}

Premlata Kumar, Qian Wu, Ken L. Chambliss, Ivan S. Yuhanna, Susanne M. Mumby, Chieko Mineo, Gregory G. Tall, and Philip W. Shaul*

Departments of Pediatricsand Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX

* To whom correspondence should be addressed. E-mail: Philip.shaul{at}utsouthwestern.edu.

Estrogen induces G protein-dependent nongenomic signaling in a variety of cell types via the activation of a plasma membrane-associated subpopulation of estrogen receptor {alpha} (ER{alpha}). Using pulldown experiments with purified recombinant proteins, we now demonstrate that ER{alpha} binds directly to G{alpha}i and G{beta}{gamma}. Mutagenesis and the addition of blocking peptide reveals that this occurs via amino acids 251-260 and 271-595 of ER{alpha} respectively. Studies of ER{alpha} complexed with heterotrimeric G proteins further show that estradiol causes the release of both G{alpha}i and G{beta}{gamma} without stimulating GTP binding to G{alpha}i. Moreover, in COS-7 cells the disruption of ER{alpha}-G{alpha}i interaction by deletion mutagenesis of ER{alpha} or expression of blocking peptide, as well as G{beta}{gamma} sequestration with {beta}-adrenergic receptor kinase C-terminus, prevents nongenomic responses to estradiol including src and erk activation. In endothelial cells the disruption of ER{alpha}-G{alpha}i interaction prevents estradiol-induced nitric oxide synthase activation and the resulting attenuation of monocyte adhesion that contributes to estrogen-related cardiovascular protection. Thus, through direct interactions ER{alpha} mediates a novel mechanism of G protein activation which provides greater diversity of function of both the steroid hormone receptor and G proteins.
Key words: endothelial nitric oxide synthase • estrogen receptor • G protein • steroid hormone receptor

NURSA Molecule Pages Link:

Nuclear Receptors:   VDR  |  ERα  |  ERβ  |  GR  |  AR
Ligands:   Calcitriol  |  Dexamethasone  |  17β-Estradiol  |  Dihydrotestosterone  |  Fulvestrant



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