Ca2+-independent protein kinase C activity is required for α1-adrenergic-receptor-mediated regulation of ribosomal protein S6 kinases in adult cardiomyocytes

Lijun Wang, Mark Rolfe, Christopher G. Proud

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

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 e 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.

Original languageEnglish
Pages (from-to)603-611
Number of pages9
JournalBiochemical Journal
Volume373
Issue number2
DOIs
Publication statusPublished - 15 Jul 2003

Keywords

  • Cardiac hypertrophy
  • Phenylephrine
  • Protein kinase C
  • Protein synthesis
  • Translation initiation
  • p70 S6 kinase

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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