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Direct Interactions with Gi and Gß Mediate Nongenomic Signaling by Estrogen Receptor

Departments of Pediatrics (P.K., Q.W., K.L.C., I.S.Y., C.M., P.W.S.) and Pharmacology (S.M.M., G.G.T.), University of Texas Southwestern Medical Center, Dallas, Texas 75390

Address all correspondence and requests for reprints to: Philip W. Shaul, Department of Pediatrics, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9063. 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 (ER). Using pull-down experiments with purified recombinant proteins, we now demonstrate that ER binds directly to Gi and Gß. Mutagenesis and the addition of blocking peptide reveals that this occurs via amino acids 251–260 and 271–595 of ER, respectively. Studies of ER complexed with heterotrimeric G proteins further show that estradiol causes the release of both Gi and Gß without stimulating GTP binding to Gi. Moreover, in COS-7 cells, the disruption of ER-Gi interaction by deletion mutagenesis of ER or expression of blocking peptide, as well as Gß sequestration with ß-adrenergic receptor kinase C terminus, prevents nongenomic responses to estradiol including src and erk activation. In endothelial cells, the disruption of ER-Gi 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 mediates a novel mechanism of G protein activation that provides greater diversity of function of both the steroid hormone receptor and G proteins.

NURSA Molecule Pages Link:

Nuclear Receptors:   VDR  |  ERα  |  ERβ  |  GR  |  AR

Ligands:   Calcitriol  |  Dexamethasone  |  17β-Estradiol  |  Dihydrotestosterone  |  Fulvestrant

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