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Dissecting the Basis of Nongenomic Activation of Endothelial Nitric Oxide Synthase by Estradiol: Role of ER Domains with Known Nuclear Functions

Department of Pediatrics, 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 at Dallas, 5323 Harry Hines Boulevard, Dallas, Texas 75390. E-mail: philip.shaul{at}utsouthwestern.edu.

Estradiol stimulates endothelial nitric oxide synthase (eNOS) via the activation of plasma membrane (PM)-associated estrogen receptor (ER) . The process requires Src and erk signaling and eNOS phosphorylation by phosphoinositide 3-kinase (PI3 kinase)-Akt kinase, with Src and PI3 kinase associating with ER upon ligand activation. To delineate the basis of nongenomic eNOS stimulation, the potential roles of ER domains necessary for classical nuclear function were investigated in COS-7 cells. In cross-linking studies, estradiol-17ß (E₂) caused PM-associated ER to form dimers. However, eNOS activation by E₂ was unaltered for a dimerization-deficient mutant ER (ERL511R). In contrast, ER mutants lacking the nuclear localization signals (NLS), NLS2,3 (ER250–274) or the DNA binding domain (ER185–251), which targeted normally to PM and caveolae/rafts, were incapable of activating eNOS. The loss of NLS2/NLS3 prevented Src and erk activation, and it altered ligand-induced PI3 kinase-ER interaction and prevented eNOS phosphorylation. Loss of the DNA binding domain did not change E₂ activation of Src or erk, but ligand-induced PI3 kinase-ER binding and eNOS phosphorylation did not occur. Thus, dimerization is not required for ER coupling to eNOS; however, NLS2/NLS3 plays a role in Src activation, and the DNA binding region is involved in the dynamic interaction between ER and PI3 kinase.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα

Ligands:   17β-Estradiol

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