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Phosphorylation of the type 1A angiotensin II receptor by G protein-coupled receptor kinases and protein kinase C.

Publication ,  Journal Article
Oppermann, M; Freedman, NJ; Alexander, RW; Lefkowitz, RJ
Published in: J Biol Chem
May 31, 1996

The type 1A angiotensin II receptor (AT1A-R), which mediates cardiovascular effects of angiotensin II, has been shown to undergo rapid agonist-induced desensitization. We investigated the potential role of second messenger-activated kinases and G protein-coupled receptor kinases (GRKs) in the regulation of this receptor. In 293 cells transfected with the AT1A-R, a 3-min challenge with angiotensin II engendered a 46% decrease in subsequent angiotensin II-stimulated phosphoinositide hydrolysis in intact cells. This agonist-induced desensitization correlated temporally and dose-dependently with the phosphorylation of the receptor to a stoichiometry of 1 mol of phosphate/mol of receptor, as assessed by immunoprecipitation of receptors from cells metabolically labeled with 32Pi. Agonist-induced receptor phosphorylation was reduced by 40-50% by either overexpression of a dominant negative K220R mutant GRK2 or treatment of the cells with the protein kinase C (PKC) inhibitor staurosporine, in a virtually additive fashion. Cellular overexpression of GRK2K220R not only inhibited agonist-induced AT1A-R phosphorylation, but also prevented receptor desensitization, as assessed by angiotensin II-stimulated GTPase activity in membranes prepared from agonist-treated and control cells. In contrast, PKC inhibition by staurosporine did not affect homologous desensitization of the AT1A-R. Overexpression of GRKs 2, 3, or 5 significantly augmented the agonist-induced AT1A-R phosphorylation 1.5- to 1.7-fold (p < 0.001). These findings suggest a role for receptor phosphorylation by one or several GRKs in the rapid agonist-induced desensitization of the AT1A-R.

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Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

May 31, 1996

Volume

271

Issue

22

Start / End Page

13266 / 13272

Location

United States

Related Subject Headings

  • Second Messenger Systems
  • Receptors, Angiotensin
  • Receptor Protein-Tyrosine Kinases
  • Rats
  • Protein Kinase C
  • Phosphorylation
  • Mutagenesis
  • Molecular Sequence Data
  • Humans
  • GTP-Binding Proteins
 

Citation

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Oppermann, M., Freedman, N. J., Alexander, R. W., & Lefkowitz, R. J. (1996). Phosphorylation of the type 1A angiotensin II receptor by G protein-coupled receptor kinases and protein kinase C. J Biol Chem, 271(22), 13266–13272. https://doi.org/10.1074/jbc.271.22.13266
Oppermann, M., N. J. Freedman, R. W. Alexander, and R. J. Lefkowitz. “Phosphorylation of the type 1A angiotensin II receptor by G protein-coupled receptor kinases and protein kinase C.J Biol Chem 271, no. 22 (May 31, 1996): 13266–72. https://doi.org/10.1074/jbc.271.22.13266.
Oppermann M, Freedman NJ, Alexander RW, Lefkowitz RJ. Phosphorylation of the type 1A angiotensin II receptor by G protein-coupled receptor kinases and protein kinase C. J Biol Chem. 1996 May 31;271(22):13266–72.
Oppermann, M., et al. “Phosphorylation of the type 1A angiotensin II receptor by G protein-coupled receptor kinases and protein kinase C.J Biol Chem, vol. 271, no. 22, May 1996, pp. 13266–72. Pubmed, doi:10.1074/jbc.271.22.13266.
Oppermann M, Freedman NJ, Alexander RW, Lefkowitz RJ. Phosphorylation of the type 1A angiotensin II receptor by G protein-coupled receptor kinases and protein kinase C. J Biol Chem. 1996 May 31;271(22):13266–13272.

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

May 31, 1996

Volume

271

Issue

22

Start / End Page

13266 / 13272

Location

United States

Related Subject Headings

  • Second Messenger Systems
  • Receptors, Angiotensin
  • Receptor Protein-Tyrosine Kinases
  • Rats
  • Protein Kinase C
  • Phosphorylation
  • Mutagenesis
  • Molecular Sequence Data
  • Humans
  • GTP-Binding Proteins