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Inhibition of beta-adrenergic receptor kinase prevents rapid homologous desensitization of beta 2-adrenergic receptors.

Publication ,  Journal Article
Lohse, MJ; Lefkowitz, RJ; Caron, MG; Benovic, JL
Published in: Proc Natl Acad Sci U S A
May 1989

Homologous (agonist-specific) desensitization of beta-adrenergic receptors (beta ARs) is accompanied by and appears to require phosphorylation of the receptors. We have recently described a novel protein kinase, beta AR kinase, which phosphorylates beta ARs in vitro in an agonist-dependent manner. This kinase is inhibited by two classes of compounds, polyanions and synthetic peptides derived from the beta 2-adrenergic receptor (beta 2AR). In this report we describe the effects of these inhibitors on the process of homologous desensitization induced by the beta-adrenergic agonist isoproterenol. Permeabilization of human epidermoid carcinoma A431 cells with digitonin was used to permit access of the charged inhibitors to the cytosol; this procedure did not interfere with the pattern of isoproterenol-induced homologous desensitization of beta 2AR-stimulated adenylyl cyclase. Inhibitors of beta AR kinase markedly inhibited homologous desensitization of beta 2ARs in the permeabilized cells. Inhibition of desensitization by heparin, the most potent of the polyanion inhibitors of beta AR kinase, occurred over the same concentration range (5-50 nM) as inhibition of purified beta AR kinase assessed in a reconstituted system. Inhibition of desensitization by heparin was accompanied by a marked reduction of receptor phosphorylation in the permeabilized cells. Whereas inhibitors of beta AR kinase inhibited homologous desensitization, inhibitors of protein kinase C and of cyclic-nucleotide-dependent protein kinases were ineffective. These data establish that phosphorylation of beta ARs by beta AR kinase is an essential step in homologous desensitization of the receptors. They further suggest a potential therapeutic value of inhibitors of beta AR kinase in inhibiting agonist-induced desensitization.

Duke Scholars

Published In

Proc Natl Acad Sci U S A

DOI

ISSN

0027-8424

Publication Date

May 1989

Volume

86

Issue

9

Start / End Page

3011 / 3015

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Receptors, Adrenergic, beta
  • Protein Kinase Inhibitors
  • Phosphorylation
  • Lung
  • Kinetics
  • Isoproterenol
  • Humans
  • Heparin
  • Drug Tolerance
 

Citation

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Lohse, M. J., Lefkowitz, R. J., Caron, M. G., & Benovic, J. L. (1989). Inhibition of beta-adrenergic receptor kinase prevents rapid homologous desensitization of beta 2-adrenergic receptors. Proc Natl Acad Sci U S A, 86(9), 3011–3015. https://doi.org/10.1073/pnas.86.9.3011
Lohse, M. J., R. J. Lefkowitz, M. G. Caron, and J. L. Benovic. “Inhibition of beta-adrenergic receptor kinase prevents rapid homologous desensitization of beta 2-adrenergic receptors.Proc Natl Acad Sci U S A 86, no. 9 (May 1989): 3011–15. https://doi.org/10.1073/pnas.86.9.3011.
Lohse MJ, Lefkowitz RJ, Caron MG, Benovic JL. Inhibition of beta-adrenergic receptor kinase prevents rapid homologous desensitization of beta 2-adrenergic receptors. Proc Natl Acad Sci U S A. 1989 May;86(9):3011–5.
Lohse, M. J., et al. “Inhibition of beta-adrenergic receptor kinase prevents rapid homologous desensitization of beta 2-adrenergic receptors.Proc Natl Acad Sci U S A, vol. 86, no. 9, May 1989, pp. 3011–15. Pubmed, doi:10.1073/pnas.86.9.3011.
Lohse MJ, Lefkowitz RJ, Caron MG, Benovic JL. Inhibition of beta-adrenergic receptor kinase prevents rapid homologous desensitization of beta 2-adrenergic receptors. Proc Natl Acad Sci U S A. 1989 May;86(9):3011–3015.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

ISSN

0027-8424

Publication Date

May 1989

Volume

86

Issue

9

Start / End Page

3011 / 3015

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Receptors, Adrenergic, beta
  • Protein Kinase Inhibitors
  • Phosphorylation
  • Lung
  • Kinetics
  • Isoproterenol
  • Humans
  • Heparin
  • Drug Tolerance