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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Kobilka, B. K. Xiao, R. P. Zheng, M. Koch, W. J. Lefkowitz, R. J. Zhu, W. Z. |
| Description | Author Affiliation: Zhu WZ ( Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.); |
| Abstract | 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. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 4 |
| Volume Number | 98 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2001-02-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Apoptosis Myocardium Cytology Protein-Serine-Threonine Kinases Receptors, Adrenergic, Beta-1 Metabolism Receptors, Adrenergic, Beta-2 Signal Transduction Physiology Animals Cell Survival Cells, Cultured GTP-Binding Protein Alpha Subunits, Gi-Go Heterotrimeric GTP-Binding Proteins Mice Mice, Knockout Mitogen-Activated Protein Kinases Phosphatidylinositol 3-Kinases Antagonists & Inhibitors Proto-Oncogene Proteins Proto-Oncogene Proteins C-akt Genetics P38 Mitogen-Activated Protein Kinases Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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