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Ligand-induced overexpression of a constitutively active beta2-adrenergic receptor: pharmacological creation of a phenotype in transgenic mice.

Publication ,  Journal Article
Samama, P; Bond, RA; Rockman, HA; Milano, CA; Lefkowitz, RJ
Published in: Proc Natl Acad Sci U S A
January 7, 1997

Transgenic overexpression (40- to 100-fold) of the wild-type human beta2-adrenergic receptor in the hearts of mice leads to a marked increase in cardiac contractility, which is apparently due to the low level of spontaneous (i.e., agonist-independent) activity inherent in the receptor. Here we report that transgenic mice expressing a mutated constitutively active form of the receptor (CAM) show no such phenotype, owing to its modest expression (3-fold above endogenous cardiac beta-adrenergic receptor levels). Surprisingly, treatment of the animals with a variety of beta-adrenergic receptor ligands leads to a 50-fold increase in CAM beta2-adrenergic receptor expression, by stabilizing the CAM beta2-adrenergic receptor protein. Receptor up-regulation leads in turn to marked increases in adenylate cyclase activity, atrial tension determined in vitro, and indices of cardiac contractility determined in vivo. These results illustrate a novel mechanism for regulating physiological responses, i.e., ligand-induced stabilization of a constitutively active but inherently unstable protein.

Duke Scholars

Published In

Proc Natl Acad Sci U S A

DOI

ISSN

0027-8424

Publication Date

January 7, 1997

Volume

94

Issue

1

Start / End Page

137 / 141

Location

United States

Related Subject Headings

  • Ventricular Function, Left
  • Up-Regulation
  • Receptors, Adrenergic, beta-2
  • Propanolamines
  • Phenotype
  • Mutation
  • Mice, Transgenic
  • Mice, Inbred C57BL
  • Mice
  • Ligands
 

Citation

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ICMJE
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Samama, P., Bond, R. A., Rockman, H. A., Milano, C. A., & Lefkowitz, R. J. (1997). Ligand-induced overexpression of a constitutively active beta2-adrenergic receptor: pharmacological creation of a phenotype in transgenic mice. Proc Natl Acad Sci U S A, 94(1), 137–141. https://doi.org/10.1073/pnas.94.1.137
Samama, P., R. A. Bond, H. A. Rockman, C. A. Milano, and R. J. Lefkowitz. “Ligand-induced overexpression of a constitutively active beta2-adrenergic receptor: pharmacological creation of a phenotype in transgenic mice.Proc Natl Acad Sci U S A 94, no. 1 (January 7, 1997): 137–41. https://doi.org/10.1073/pnas.94.1.137.
Samama P, Bond RA, Rockman HA, Milano CA, Lefkowitz RJ. Ligand-induced overexpression of a constitutively active beta2-adrenergic receptor: pharmacological creation of a phenotype in transgenic mice. Proc Natl Acad Sci U S A. 1997 Jan 7;94(1):137–41.
Samama, P., et al. “Ligand-induced overexpression of a constitutively active beta2-adrenergic receptor: pharmacological creation of a phenotype in transgenic mice.Proc Natl Acad Sci U S A, vol. 94, no. 1, Jan. 1997, pp. 137–41. Pubmed, doi:10.1073/pnas.94.1.137.
Samama P, Bond RA, Rockman HA, Milano CA, Lefkowitz RJ. Ligand-induced overexpression of a constitutively active beta2-adrenergic receptor: pharmacological creation of a phenotype in transgenic mice. Proc Natl Acad Sci U S A. 1997 Jan 7;94(1):137–141.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

ISSN

0027-8424

Publication Date

January 7, 1997

Volume

94

Issue

1

Start / End Page

137 / 141

Location

United States

Related Subject Headings

  • Ventricular Function, Left
  • Up-Regulation
  • Receptors, Adrenergic, beta-2
  • Propanolamines
  • Phenotype
  • Mutation
  • Mice, Transgenic
  • Mice, Inbred C57BL
  • Mice
  • Ligands