Skip to main content
Journal cover image

Structural basis for receptor subtype-specific regulation revealed by a chimeric beta 3/beta 2-adrenergic receptor.

Publication ,  Journal Article
Liggett, SB; Freedman, NJ; Schwinn, DA; Lefkowitz, RJ
Published in: Proc Natl Acad Sci U S A
April 15, 1993

The physiological significance of multiple G-protein-coupled receptor subtypes, such as the beta-adrenergic receptors (beta ARs), remains obscure, since in many cases several subtypes activate the same effector and utilize the same physiological agonists. We inspected the deduced amino acid sequences of the beta AR subtypes for variations in the determinants for agonist regulation as a potential basis for subtype differentiation. Whereas the beta 2AR has a C terminus containing 11 serine and threonine residues representing potential sites for beta AR kinase phosphorylation, which mediates rapid agonist-promoted desensitization, only 3 serines are present in the comparable region of the beta 3AR, and they are in a nonfavorable context. The beta 3AR also lacks sequence homology in regions which are important for agonist-mediated sequestration and down-regulation of the beta 2AR, although such determinants are less well defined. We therefore tested the idea that the agonist-induced regulatory properties of the two receptors might differ by expressing both subtypes in CHW cells and exposing them to the agonist isoproterenol. The beta 3AR did not display short-term agonist-promoted functional desensitization or sequestration, or long-term down-regulation. To assign a structural basis for these subtype-specific differences in agonist regulation, we constructed a chimeric beta 3/beta 2AR which comprised the beta 3AR up to proline-365 of the cytoplasmic tail and the C terminus of the beta 2AR. When cells expressing this chimeric beta 3/beta 2AR were exposed to isoproterenol, functional desensitization was observed. Whole-cell phosphorylation studies showed that the beta 2AR displayed agonist-dependent phosphorylation, but no such phosphorylation could be demonstrated with the beta 3AR, even when beta AR kinase was overexpressed. In contrast, the chimeric beta 3/beta 2AR did display agonist-dependent phosphorylation, consistent with its functional desensitization. In addition to conferring functional desensitization and phosphorylation to the beta 3AR, the C-terminal tail of the beta 2AR also conferred agonist-promoted sequestration and long-term receptor down-regulation.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Proc Natl Acad Sci U S A

DOI

ISSN

0027-8424

Publication Date

April 15, 1993

Volume

90

Issue

8

Start / End Page

3665 / 3669

Location

United States

Related Subject Headings

  • Restriction Mapping
  • Recombinant Fusion Proteins
  • Receptors, Adrenergic, beta
  • Radioligand Assay
  • Protein Conformation
  • Pindolol
  • Phosphorylation
  • Molecular Sequence Data
  • Kinetics
  • Isoproterenol
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Liggett, S. B., Freedman, N. J., Schwinn, D. A., & Lefkowitz, R. J. (1993). Structural basis for receptor subtype-specific regulation revealed by a chimeric beta 3/beta 2-adrenergic receptor. Proc Natl Acad Sci U S A, 90(8), 3665–3669. https://doi.org/10.1073/pnas.90.8.3665
Liggett, S. B., N. J. Freedman, D. A. Schwinn, and R. J. Lefkowitz. “Structural basis for receptor subtype-specific regulation revealed by a chimeric beta 3/beta 2-adrenergic receptor.Proc Natl Acad Sci U S A 90, no. 8 (April 15, 1993): 3665–69. https://doi.org/10.1073/pnas.90.8.3665.
Liggett SB, Freedman NJ, Schwinn DA, Lefkowitz RJ. Structural basis for receptor subtype-specific regulation revealed by a chimeric beta 3/beta 2-adrenergic receptor. Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3665–9.
Liggett, S. B., et al. “Structural basis for receptor subtype-specific regulation revealed by a chimeric beta 3/beta 2-adrenergic receptor.Proc Natl Acad Sci U S A, vol. 90, no. 8, Apr. 1993, pp. 3665–69. Pubmed, doi:10.1073/pnas.90.8.3665.
Liggett SB, Freedman NJ, Schwinn DA, Lefkowitz RJ. Structural basis for receptor subtype-specific regulation revealed by a chimeric beta 3/beta 2-adrenergic receptor. Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3665–3669.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

ISSN

0027-8424

Publication Date

April 15, 1993

Volume

90

Issue

8

Start / End Page

3665 / 3669

Location

United States

Related Subject Headings

  • Restriction Mapping
  • Recombinant Fusion Proteins
  • Receptors, Adrenergic, beta
  • Radioligand Assay
  • Protein Conformation
  • Pindolol
  • Phosphorylation
  • Molecular Sequence Data
  • Kinetics
  • Isoproterenol