The α1-adrenergic agonist, phenylephrine (PE), exerts hypertrophic effects in the myocardium and activates protein synthesis. Both Ca2+-dependent protein kinase C (PKC, PKCα) and Ca2+-independent PKC isoforms (PKCδ and ε) are detectably expressed in adult rat cardiomyocytes. Stimulation of the α1-adrenergic receptor by PE results in activation of Ca2+-independent PKCs, as demonstrated by translocation of the δ and ε isoenzymes from cytosol to membrane fractions. PE also induces activation of p70 ribosomal protein S6 kinases (S6K1 and 2) in adult cardiomyocytes. We have studied the role of Ca2+-independent PKCs in the regulation of S6K activity by PE. Activation of S6K1/2 by PE was blocked by the broad-spectrum PKC inhibitor bisindolylmaleimide (BIM) I, whereas Gö6976, a compound that only inhibits Ca2+-dependent PKCs, did not inhibit S6K activation. Rottlerin, which selectively inhibits PKCδ, also prevented PE-induced S6K activation. The isoform-specific PKC inhibitors had similar effects on the phosphorylation of eukaryotic initiation factor 4E (eIF4E)-binding protein 1, a translation repressor that, like the S6Ks, lies downstream of the mammalian target of rapamycin (mTOR). Infection of cells with adenoviruses encoding dominant-negative PKCδ or ε inhibited the activation of extracellular-signal-regulated kinase (ERK) by PE, and also inhibited the activation and/or phosphorylation of S6Ks 1 and 2. The PE-induced activation of protein synthesis was abolished by BIM I and markedly attenuated by rottlerin. Our data thus suggest that Ca2+-independent PKC isoforms play an important role in coupling the α1-adrenergic receptor to mTOR signalling and protein synthesis in adult cardiomyocytes.
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July 2003
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Research Article|
July 15 2003
Ca2+-independent protein kinase C activity is required for alpha1-adrenergic-receptor-mediated regulation of ribosomal protein S6 kinases in adult cardiomyocytes
Lijun WANG;
Lijun WANG
Division of Molecular Physiology, School of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K.
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Mark ROLFE;
Mark ROLFE
Division of Molecular Physiology, School of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K.
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Christopher G. PROUD
Christopher G. PROUD
1
Division of Molecular Physiology, School of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K.
1To whom correspondence should be addressed (e-mail c.g.proud@dundee.ac.uk).
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Publisher: Portland Press Ltd
Received:
March 24 2003
Revision Received:
April 29 2003
Accepted:
April 30 2003
Accepted Manuscript online:
April 30 2003
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2003
2003
Biochem J (2003) 373 (2): 603–611.
Article history
Received:
March 24 2003
Revision Received:
April 29 2003
Accepted:
April 30 2003
Accepted Manuscript online:
April 30 2003
Citation
Lijun WANG, Mark ROLFE, Christopher G. PROUD; Ca2+-independent protein kinase C activity is required for alpha1-adrenergic-receptor-mediated regulation of ribosomal protein S6 kinases in adult cardiomyocytes. Biochem J 15 July 2003; 373 (2): 603–611. doi: https://doi.org/10.1042/bj20030454
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