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Endothelin-1 activates endothelial cell nitric-oxide synthase via heterotrimeric G-protein betagamma subunit signaling to protein jinase B/Akt.

Publication ,  Journal Article
Liu, S; Premont, RT; Kontos, CD; Huang, J; Rockey, DC
Published in: J Biol Chem
December 12, 2003

Endothelin-1 has dual vasoactive effects, mediating vasoconstriction via ETA receptor activation of vascular smooth muscle cells and vasorelaxation via ETB receptor activation of endothelial cells. Although it is commonly accepted that endothelin-1 binding to endothelial cell ETB receptors stimulates nitric oxide (NO) synthesis and subsequent smooth muscle relaxation, the signaling pathways downstream of ETB receptor activation are unknown. Here, using a model in which we have utilized isolated primary endothelial cells, we demonstrate that ET-1 binding to sinusoidal endothelial cell ETB receptors led to increased protein kinase B/Akt phosphorylation, endothelial cell nitric-oxide synthase (eNOS) phosphorylation, and NO synthesis. Furthermore, eNOS activation was not dependent on tyrosine phosphorylation, and pretreatment of endothelial cells with pertussis toxin as well as overexpression of a dominant negative G-protein-coupled receptor kinase construct that sequesters betagamma subunits inhibited Akt phosphorylation and NO synthesis. Taken together, the data elucidate a G-protein-coupled receptor signaling pathway for ETB receptor-mediated NO production and call attention to the absolute requirement for heterotrimeric G-protein betagamma subunits in this cascade.

Duke Scholars

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

December 12, 2003

Volume

278

Issue

50

Start / End Page

49929 / 49935

Location

United States

Related Subject Headings

  • Tyrosine
  • Time Factors
  • Signal Transduction
  • Receptors, Endothelin
  • Rats, Sprague-Dawley
  • Rats
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins
  • Protein Structure, Tertiary
  • Protein Serine-Threonine Kinases
 

Citation

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Liu, S., Premont, R. T., Kontos, C. D., Huang, J., & Rockey, D. C. (2003). Endothelin-1 activates endothelial cell nitric-oxide synthase via heterotrimeric G-protein betagamma subunit signaling to protein jinase B/Akt. J Biol Chem, 278(50), 49929–49935. https://doi.org/10.1074/jbc.M306930200
Liu, Songling, Richard T. Premont, Christopher D. Kontos, Jianhua Huang, and Don C. Rockey. “Endothelin-1 activates endothelial cell nitric-oxide synthase via heterotrimeric G-protein betagamma subunit signaling to protein jinase B/Akt.J Biol Chem 278, no. 50 (December 12, 2003): 49929–35. https://doi.org/10.1074/jbc.M306930200.
Liu, Songling, et al. “Endothelin-1 activates endothelial cell nitric-oxide synthase via heterotrimeric G-protein betagamma subunit signaling to protein jinase B/Akt.J Biol Chem, vol. 278, no. 50, Dec. 2003, pp. 49929–35. Pubmed, doi:10.1074/jbc.M306930200.
Liu S, Premont RT, Kontos CD, Huang J, Rockey DC. Endothelin-1 activates endothelial cell nitric-oxide synthase via heterotrimeric G-protein betagamma subunit signaling to protein jinase B/Akt. J Biol Chem. 2003 Dec 12;278(50):49929–49935.

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

December 12, 2003

Volume

278

Issue

50

Start / End Page

49929 / 49935

Location

United States

Related Subject Headings

  • Tyrosine
  • Time Factors
  • Signal Transduction
  • Receptors, Endothelin
  • Rats, Sprague-Dawley
  • Rats
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins
  • Protein Structure, Tertiary
  • Protein Serine-Threonine Kinases