TY - JOUR
T1 - Rapid activation of endothelial NO synthase by estrogen
T2 - Evidence for a steroid receptor fast-action complex (SRFC) in caveolae
AU - Chambliss, Ken L.
AU - Shaul, Philip W.
N1 - Funding Information:
The authors would like to thank the colleagues and collaborators who have contributed to the data summarized in this review. These include Richard G.W. Anderson, Zohre German, Pingsheng Liu, Michael E. Mendelsohn, Chieko Mineo, Susanne M. Mumby, Todd S. Sherman, Myra H. Wyckoff, and Ivan S. Yuhanna. The authors would also like to thank Marilyn Dixon for preparing this manuscript. This work was supported by National Institutes of Health grants HL58888, HL53546, and HD30276, the Lowe Foundation, and the Crystal Charity Ball.
PY - 2002
Y1 - 2002
N2 - 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.
AB - 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.
KW - Caveolae
KW - Endothelium
KW - Estrogen
KW - Estrogen receptor
KW - G protein
KW - Nitric oxide synthase
KW - Steroid
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U2 - 10.1016/S0039-128X(01)00177-5
DO - 10.1016/S0039-128X(01)00177-5
M3 - Article
C2 - 11960616
AN - SCOPUS:0036230688
SN - 0039-128X
VL - 67
SP - 413
EP - 419
JO - Steroids
JF - Steroids
IS - 6
ER -