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Transgenic mice with cardiac overexpression of alpha1B-adrenergic receptors. In vivo alpha1-adrenergic receptor-mediated regulation of beta-adrenergic signaling.

Publication ,  Journal Article
Akhter, SA; Milano, CA; Shotwell, KF; Cho, MC; Rockman, HA; Lefkowitz, RJ; Koch, WJ
Published in: J Biol Chem
August 22, 1997

Transgenic mice were generated with cardiac-specific overexpression of the wild-type (WT) alpha1B-adrenergic receptor (AR) using the murine alpha-myosin heavy chain gene promoter. Previously, we described transgenic mice with alpha-myosin heavy chain-directed expression of a constitutively active mutant alpha1B-AR that had a phenotype of myocardial hypertrophy (Milano, C. A., Dolber, P. C., Rockman, H. A., Bond, R. A., Venable M. E., Allen, L. F., and Lefkowitz, R. J. (1994) Proc. Natl. Acad. Sci. U. S. A. 91, 10109-10113). In animals with >40-fold WT alpha1-AR overexpression, basal myocardial diacylglycerol content was significantly increased, indicating enhanced alpha1-adrenergic signaling and phospholipase C activity. In contrast to the mice overexpressing constitutively active mutant alpha1B-ARs, the hearts of these mice did not develop cardiac hypertrophy despite an 8-fold increase in ventricular mRNA for atrial natriuretic factor. In vivo physiology was studied in anesthetized intact animals and showed left ventricular contractility in response to the beta-agonist isoproterenol to be significantly depressed in animals overexpressing WT alpha1B-ARs. Membranes purified from the hearts of WT alpha1BAR-overexpressing mice demonstrated significantly attenuated adenylyl cyclase activity basally and after stimulation with isoproterenol, norepinephrine, or phenylephrine. Interestingly, these in vitro changes in signaling were reversed after treating the mice with pertussis toxin, suggesting that the extraordinarily high levels of WT alpha1B-ARs can lead to coupling to pertussis toxin-sensitive G proteins. Another potential contributor to the observed decreased myocardial signaling and function could be enhanced beta-AR desensitization as beta-adrenergic receptor kinase (betaARK1) activity was found to be significantly elevated (>3-fold) in myocardial extracts isolated from WT alpha1B-AR-overexpressing mice. This type of altered signal transduction may become critical in disease conditions such as heart failure where betaARK1 levels are elevated and beta-ARs are down-regulated, leading to a higher percentage of cardiac alpha1-ARs. Thus, these mice serve as a unique experimental model to study the in vivo interactions between alpha- and beta-ARs in the heart.

Duke Scholars

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

August 22, 1997

Volume

272

Issue

34

Start / End Page

21253 / 21259

Location

United States

Related Subject Headings

  • beta-Adrenergic Receptor Kinases
  • Virulence Factors, Bordetella
  • Signal Transduction
  • Sarcolemma
  • Receptors, Adrenergic, beta
  • Receptors, Adrenergic, alpha-1
  • RNA, Messenger
  • Pertussis Toxin
  • Myocardium
  • Myocardial Contraction
 

Citation

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MLA
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Akhter, S. A., Milano, C. A., Shotwell, K. F., Cho, M. C., Rockman, H. A., Lefkowitz, R. J., & Koch, W. J. (1997). Transgenic mice with cardiac overexpression of alpha1B-adrenergic receptors. In vivo alpha1-adrenergic receptor-mediated regulation of beta-adrenergic signaling. J Biol Chem, 272(34), 21253–21259. https://doi.org/10.1074/jbc.272.34.21253
Akhter, S. A., C. A. Milano, K. F. Shotwell, M. C. Cho, H. A. Rockman, R. J. Lefkowitz, and W. J. Koch. “Transgenic mice with cardiac overexpression of alpha1B-adrenergic receptors. In vivo alpha1-adrenergic receptor-mediated regulation of beta-adrenergic signaling.J Biol Chem 272, no. 34 (August 22, 1997): 21253–59. https://doi.org/10.1074/jbc.272.34.21253.
Akhter SA, Milano CA, Shotwell KF, Cho MC, Rockman HA, Lefkowitz RJ, et al. Transgenic mice with cardiac overexpression of alpha1B-adrenergic receptors. In vivo alpha1-adrenergic receptor-mediated regulation of beta-adrenergic signaling. J Biol Chem. 1997 Aug 22;272(34):21253–9.
Akhter, S. A., et al. “Transgenic mice with cardiac overexpression of alpha1B-adrenergic receptors. In vivo alpha1-adrenergic receptor-mediated regulation of beta-adrenergic signaling.J Biol Chem, vol. 272, no. 34, Aug. 1997, pp. 21253–59. Pubmed, doi:10.1074/jbc.272.34.21253.
Akhter SA, Milano CA, Shotwell KF, Cho MC, Rockman HA, Lefkowitz RJ, Koch WJ. Transgenic mice with cardiac overexpression of alpha1B-adrenergic receptors. In vivo alpha1-adrenergic receptor-mediated regulation of beta-adrenergic signaling. J Biol Chem. 1997 Aug 22;272(34):21253–21259.

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

August 22, 1997

Volume

272

Issue

34

Start / End Page

21253 / 21259

Location

United States

Related Subject Headings

  • beta-Adrenergic Receptor Kinases
  • Virulence Factors, Bordetella
  • Signal Transduction
  • Sarcolemma
  • Receptors, Adrenergic, beta
  • Receptors, Adrenergic, alpha-1
  • RNA, Messenger
  • Pertussis Toxin
  • Myocardium
  • Myocardial Contraction