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Dual modulation of cell survival and cell death by beta(2)-adrenergic signaling in adult mouse cardiac myocytes.

Publication ,  Journal Article
Zhu, WZ; Zheng, M; Koch, WJ; Lefkowitz, RJ; Kobilka, BK; Xiao, RP
Published in: Proc Natl Acad Sci U S A
February 13, 2001

The goal of this study was to determine whether beta(1)-adrenergic receptor (AR) and beta(2)-AR differ in regulating cardiomyocyte survival and apoptosis and, if so, to explore underlying mechanisms. One potential mechanism is that cardiac beta(2)-AR can activate both G(s) and G(i) proteins, whereas cardiac beta(1)-AR couples only to G(s). To avoid complicated crosstalk between beta-AR subtypes, we expressed beta(1)-AR or beta(2)-AR individually in adult beta(1)/beta(2)-AR double knockout mouse cardiac myocytes by using adenoviral gene transfer. Stimulation of beta(1)-AR, but not beta(2)-AR, markedly induced myocyte apoptosis, as indicated by increased terminal deoxynucleotidyltransferase-mediated UTP end labeling or Hoechst staining positive cells and DNA fragmentation. In contrast, beta(2)-AR (but not beta(1)-AR) stimulation elevated the activity of Akt, a powerful survival signal; this effect was fully abolished by inhibiting G(i), G(beta gamma), or phosphoinositide 3 kinase (PI3K) with pertussis toxin, beta ARK-ct (a peptide inhibitor of G(beta gamma)), or LY294002, respectively. This indicates that beta(2)-AR activates Akt via a G(i)-G(beta gamma)-PI3K pathway. More importantly, inhibition of the G(i)-G(beta gamma)-PI3K-Akt pathway converts beta(2)-AR signaling from survival to apoptotic. Thus, stimulation of a single class of receptors, beta(2)-ARs, elicits concurrent apoptotic and survival signals in cardiac myocytes. The survival effect appears to predominate and is mediated by the G(i)-G(beta gamma)-PI3K-Akt signaling pathway.

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Published In

Proc Natl Acad Sci U S A

DOI

ISSN

0027-8424

Publication Date

February 13, 2001

Volume

98

Issue

4

Start / End Page

1607 / 1612

Location

United States

Related Subject Headings

  • p38 Mitogen-Activated Protein Kinases
  • Signal Transduction
  • Receptors, Adrenergic, beta-2
  • Receptors, Adrenergic, beta-1
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins
  • Protein Serine-Threonine Kinases
  • Phosphoinositide-3 Kinase Inhibitors
  • Myocardium
  • Mitogen-Activated Protein Kinases
 

Citation

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Zhu, W. Z., Zheng, M., Koch, W. J., Lefkowitz, R. J., Kobilka, B. K., & Xiao, R. P. (2001). Dual modulation of cell survival and cell death by beta(2)-adrenergic signaling in adult mouse cardiac myocytes. Proc Natl Acad Sci U S A, 98(4), 1607–1612. https://doi.org/10.1073/pnas.98.4.1607
Zhu, W. Z., M. Zheng, W. J. Koch, R. J. Lefkowitz, B. K. Kobilka, and R. P. Xiao. “Dual modulation of cell survival and cell death by beta(2)-adrenergic signaling in adult mouse cardiac myocytes.Proc Natl Acad Sci U S A 98, no. 4 (February 13, 2001): 1607–12. https://doi.org/10.1073/pnas.98.4.1607.
Zhu WZ, Zheng M, Koch WJ, Lefkowitz RJ, Kobilka BK, Xiao RP. Dual modulation of cell survival and cell death by beta(2)-adrenergic signaling in adult mouse cardiac myocytes. Proc Natl Acad Sci U S A. 2001 Feb 13;98(4):1607–12.
Zhu, W. Z., et al. “Dual modulation of cell survival and cell death by beta(2)-adrenergic signaling in adult mouse cardiac myocytes.Proc Natl Acad Sci U S A, vol. 98, no. 4, Feb. 2001, pp. 1607–12. Pubmed, doi:10.1073/pnas.98.4.1607.
Zhu WZ, Zheng M, Koch WJ, Lefkowitz RJ, Kobilka BK, Xiao RP. Dual modulation of cell survival and cell death by beta(2)-adrenergic signaling in adult mouse cardiac myocytes. Proc Natl Acad Sci U S A. 2001 Feb 13;98(4):1607–1612.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

ISSN

0027-8424

Publication Date

February 13, 2001

Volume

98

Issue

4

Start / End Page

1607 / 1612

Location

United States

Related Subject Headings

  • p38 Mitogen-Activated Protein Kinases
  • Signal Transduction
  • Receptors, Adrenergic, beta-2
  • Receptors, Adrenergic, beta-1
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins
  • Protein Serine-Threonine Kinases
  • Phosphoinositide-3 Kinase Inhibitors
  • Myocardium
  • Mitogen-Activated Protein Kinases