Rapid activation of endothelial NO synthase by estrogen: Evidence for a steroid receptor fast-action complex (SRFC) in caveolae

Ken L. Chambliss, Philip W. Shaul

Research output: Contribution to journalArticle

85 Scopus citations

Abstract

Estrogen has important atheroprotective and vasoactive properties related to its capacity to stimulate nitric oxide (NO) production by endothelial NO synthase. Previous work has shown that these effects are mediated by estrogen receptor (ER) α functioning in a nongenomic manner via calcium-dependent, MAP kinase-dependent mechanisms. Recent studies have demonstrated that estradiol (E2) activates eNOS in isolated endothelial plasma membranes in the absence of added calcium, calmodulin or eNOS cofactors. Studies of blockade by ICI 182,780 and by ERα antibody, and also immunoidentification experiments indicate that the process is mediated by a subpopulation of plasma membrane-associated ERα. Fractionation of endothelial cell plasma membranes has further revealed that ERα protein is localized to caveolae, and that E2 causes stimulation of eNOS in isolated caveolae which is ER-dependent and calcium-dependent, whereas noncaveolae membranes are insensitive. Furthermore, in intact endothelial cells the activation of eNOS by E2 is prevented by pertussis toxin, and exogenous GDPβS inhibits the response in isolated plasma membranes. Coimmunoprecipitation studies have shown that E2 exposure causes interaction between ERα and Gαi on the plasma membrane, and eNOS activation by E2 is enhanced by overexpression of Gαi and attenuated by expression of a protein regulator of G protein signaling (RGS), RGS4. Thus, a subpopulation of ERα is localized to caveolae in endothelial cells, where they are coupled via Gαi to eNOS in a functional signaling module. Emphasizing the dependence on cell surface-associated receptors, these observations provide evidence for the existence of a steroid receptor fast-action complex, or SRFC, in caveolae.

Original languageEnglish (US)
Pages (from-to)413-419
Number of pages7
JournalSteroids
Volume67
Issue number6
DOIs
StatePublished - Apr 25 2002

Keywords

  • Caveolae
  • Endothelium
  • Estrogen
  • Estrogen receptor
  • G protein
  • Nitric oxide synthase
  • Steroid

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Endocrinology
  • Pharmacology
  • Clinical Biochemistry
  • Organic Chemistry

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