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J. Biol. Chem. 276 (29): 27071-27076

© 2001 by The American Society for Biochemistry and Molecular Biology, Inc.

Plasma Membrane Estrogen Receptors Are Coupled to Endothelial Nitric-oxide Synthase through Galpha i*

Myra H. WyckoffDagger , Ken L. ChamblissDagger , Chieko MineoDagger , Ivan S. YuhannaDagger , Michael E. Mendelsohn§, Susanne M. Mumby, and Philip W. ShaulDagger ||

From the Departments of Dagger  Pediatrics and  Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390 and the § Molecular Cardiology Research Institute, New England Medical Center and Tufts University School of Medicine, Boston, Massachusetts 02111

Estrogen causes rapid endothelial nitric oxide (NO) production because of the activation of plasma membrane-associated estrogen receptors (ER) coupled to endothelial NO synthase (eNOS). In the present study, we determined the role of G proteins in eNOS activation by estrogen. Estradiol-17beta (E2, 10-8 M) and acetylcholine (10-5 M) caused comparable increases in NOS activity (15 min) in intact endothelial cells that were fully blocked by pertussis toxin (Ptox). In addition, exogenous guanosine 5'-O-(2- thiodiphosphate) inhibited E2-mediated eNOS stimulation in isolated endothelial plasma membranes, and Ptox prevented enzyme activation by E2 in COS-7 cells expressing ERalpha and eNOS. Coimmunoprecipitation studies of plasma membranes from COS-7 cells transfected with ERalpha and specific Galpha proteins demonstrated E2-stimulated interaction between ERalpha and Galpha i but not between ERalpha and either Galpha q or Galpha s; the observed ERalpha -Galpha i interaction was blocked by the ER antagonist ICI 182,780 and by Ptox. E2-stimulated ERalpha -Galpha i interaction was also demonstrable in endothelial cell plasma membranes. Cotransfection of Galpha i into COS-7 cells expressing ERalpha and eNOS yielded a 3-fold increase in E2-mediated eNOS stimulation, whereas cotransfection with a protein regulator of G protein signaling, RGS4, inhibited the E2 response. These findings indicate that eNOS stimulation by E2 requires plasma membrane ERalpha coupling to Galpha i and that activated Galpha i mediates the requisite downstream signaling events. Thus, novel G protein coupling enables a subpopulation of ERalpha to initiate signal transduction at the cell surface. Similar mechanisms may underly the nongenomic actions of other steroid hormones.


* This work was supported by National Institutes of Health Grants HL58888, HL53546, and HD30276 (to P. W. S.), GM50515 (to S. M. M.), and HL56069 and HL59953 (to M. E. M). The project was supported in part by the Lowe Foundation.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

|| To whom correspondence should be addressed. Tel.: 214-648-2015; Fax: 214-648-2481; E-mail: pshaul@mednet.swmed.edu.


Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.

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