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A small region of the beta-adrenergic receptor is selectively involved in its rapid regulation.

Publication ,  Journal Article
Hausdorff, WP; Campbell, PT; Ostrowski, J; Yu, SS; Caron, MG; Lefkowitz, RJ
Published in: Proc Natl Acad Sci U S A
April 15, 1991

Plasma membrane receptors that couple to guanine nucleotide-binding regulatory proteins (G proteins) undergo a variety of rapid (minutes) and longer term (hours) regulatory processes induced by ligands. For the beta 2-adrenergic receptor (beta 2AR), the rapid processes include functional desensitization, mediated by phosphorylation of the receptor by the cAMP-dependent protein kinase and the beta-adrenergic receptor kinase, as well as a loss of hydrophilic ligand binding proposed to represent sequestration of receptors into a cellular compartment distinct from the plasma membrane. The slower processes include beta 2AR down-regulation (i.e., a decrease in the total cellular complement of receptors). It is not yet known whether beta 2AR phosphorylation and/or sequestration are prerequisites for down-regulation of the receptor. Like other G protein-coupled receptors, the beta 2AR molecule spans the plasma membrane seven times, and the cytoplasmic carboxyl-terminal domain has been proposed to contain molecular determinants for each of these regulatory processes. We replaced four serine and threonine residues located within a 10-amino acid segment of this domain of beta 2AR and thereby prevented agonist-promoted phosphorylation, sequestration, and rapid desensitization of the adenylyl cyclase response. In contrast, these mutations did not affect functional coupling to the stimulatory G protein Gs or long-term down-regulation. These findings thus define a small, hitherto unappreciated region of the receptor molecule that may selectively subserve its rapid regulation. In addition, with the demonstration that beta 2AR does not have to be phosphorylated or sequestered in order to enter the down-regulation pathway, the results suggest that the classical receptor endocytosis model may not be appropriate for beta 2AR regulation.

Duke Scholars

Published In

Proc Natl Acad Sci U S A

DOI

ISSN

0027-8424

Publication Date

April 15, 1991

Volume

88

Issue

8

Start / End Page

2979 / 2983

Location

United States

Related Subject Headings

  • Time Factors
  • Structure-Activity Relationship
  • Signal Transduction
  • Receptors, Adrenergic, beta
  • Phosphorylation
  • Isoproterenol
  • In Vitro Techniques
  • Humans
  • GTP-Binding Proteins
  • Down-Regulation
 

Citation

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Hausdorff, W. P., Campbell, P. T., Ostrowski, J., Yu, S. S., Caron, M. G., & Lefkowitz, R. J. (1991). A small region of the beta-adrenergic receptor is selectively involved in its rapid regulation. Proc Natl Acad Sci U S A, 88(8), 2979–2983. https://doi.org/10.1073/pnas.88.8.2979
Hausdorff, W. P., P. T. Campbell, J. Ostrowski, S. S. Yu, M. G. Caron, and R. J. Lefkowitz. “A small region of the beta-adrenergic receptor is selectively involved in its rapid regulation.Proc Natl Acad Sci U S A 88, no. 8 (April 15, 1991): 2979–83. https://doi.org/10.1073/pnas.88.8.2979.
Hausdorff WP, Campbell PT, Ostrowski J, Yu SS, Caron MG, Lefkowitz RJ. A small region of the beta-adrenergic receptor is selectively involved in its rapid regulation. Proc Natl Acad Sci U S A. 1991 Apr 15;88(8):2979–83.
Hausdorff, W. P., et al. “A small region of the beta-adrenergic receptor is selectively involved in its rapid regulation.Proc Natl Acad Sci U S A, vol. 88, no. 8, Apr. 1991, pp. 2979–83. Pubmed, doi:10.1073/pnas.88.8.2979.
Hausdorff WP, Campbell PT, Ostrowski J, Yu SS, Caron MG, Lefkowitz RJ. A small region of the beta-adrenergic receptor is selectively involved in its rapid regulation. Proc Natl Acad Sci U S A. 1991 Apr 15;88(8):2979–2983.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

ISSN

0027-8424

Publication Date

April 15, 1991

Volume

88

Issue

8

Start / End Page

2979 / 2983

Location

United States

Related Subject Headings

  • Time Factors
  • Structure-Activity Relationship
  • Signal Transduction
  • Receptors, Adrenergic, beta
  • Phosphorylation
  • Isoproterenol
  • In Vitro Techniques
  • Humans
  • GTP-Binding Proteins
  • Down-Regulation