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Phosphorylation sites on two domains of the beta 2-adrenergic receptor are involved in distinct pathways of receptor desensitization.

Publication ,  Journal Article
Hausdorff, WP; Bouvier, M; O'Dowd, BF; Irons, GP; Caron, MG; Lefkowitz, RJ
Published in: J Biol Chem
July 25, 1989

Continuous exposure of cells to neurotransmitter or hormone agonists often results in a rapid desensitization of the cellular response. For example, pretreatment of Chinese hamster fibroblasts (CHW cells) expressing beta 2-adrenergic receptors (beta 2AR) with low (nanomolar) concentrations of isoproterenol, a beta-adrenergic agonist, causes decreases in the sensitivity of the cellular adenylyl cyclase response to the agonist, without changing the maximal responsiveness. In contrast, exposure of CHW cells to high (micromolar) concentrations of isoproterenol results in decreases in both sensitivity and the maximal responsiveness to agonist. To explore the role(s) of receptor phosphorylation in these processes, we expressed in CHW cells three mutant beta 2AR genes encoding receptors lacking putative phosphorylation sites for the cAMP-dependent protein kinase A and/or the cAMP-independent beta 2AR kinase. Using these mutants we found that exposure of cells to low concentrations of agonist appears to preferentially induce phosphorylation at protein kinase A sites. This phosphorylation correlates with the decreased sensitivity to agonist stimulation of the adenylyl cyclase response. At higher agonist concentrations phosphorylation on both the beta 2AR kinase and protein kinase A sites occurs, and only then is the maximal cyclase responsiveness elicited by agonist reduced. We conclude that low or high concentrations of agonist elicit phosphorylation of beta 2AR on distinct domains, with different implications for the functional coupling of the receptors with effector molecules.

Duke Scholars

Published In

J Biol Chem

ISSN

0021-9258

Publication Date

July 25, 1989

Volume

264

Issue

21

Start / End Page

12657 / 12665

Location

United States

Related Subject Headings

  • Transfection
  • Recombinant Proteins
  • Receptors, Adrenergic, beta
  • Phosphorylation
  • Mutation
  • Molecular Sequence Data
  • Kinetics
  • Isoproterenol
  • Humans
  • Cell Membrane
 

Citation

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Hausdorff, W. P., Bouvier, M., O’Dowd, B. F., Irons, G. P., Caron, M. G., & Lefkowitz, R. J. (1989). Phosphorylation sites on two domains of the beta 2-adrenergic receptor are involved in distinct pathways of receptor desensitization. J Biol Chem, 264(21), 12657–12665.
Hausdorff, W. P., M. Bouvier, B. F. O’Dowd, G. P. Irons, M. G. Caron, and R. J. Lefkowitz. “Phosphorylation sites on two domains of the beta 2-adrenergic receptor are involved in distinct pathways of receptor desensitization.J Biol Chem 264, no. 21 (July 25, 1989): 12657–65.
Hausdorff WP, Bouvier M, O’Dowd BF, Irons GP, Caron MG, Lefkowitz RJ. Phosphorylation sites on two domains of the beta 2-adrenergic receptor are involved in distinct pathways of receptor desensitization. J Biol Chem. 1989 Jul 25;264(21):12657–65.
Hausdorff, W. P., et al. “Phosphorylation sites on two domains of the beta 2-adrenergic receptor are involved in distinct pathways of receptor desensitization.J Biol Chem, vol. 264, no. 21, July 1989, pp. 12657–65.
Hausdorff WP, Bouvier M, O’Dowd BF, Irons GP, Caron MG, Lefkowitz RJ. Phosphorylation sites on two domains of the beta 2-adrenergic receptor are involved in distinct pathways of receptor desensitization. J Biol Chem. 1989 Jul 25;264(21):12657–12665.

Published In

J Biol Chem

ISSN

0021-9258

Publication Date

July 25, 1989

Volume

264

Issue

21

Start / End Page

12657 / 12665

Location

United States

Related Subject Headings

  • Transfection
  • Recombinant Proteins
  • Receptors, Adrenergic, beta
  • Phosphorylation
  • Mutation
  • Molecular Sequence Data
  • Kinetics
  • Isoproterenol
  • Humans
  • Cell Membrane