Ca2+-independent protein kinase C activity is required for alpha(1)-adrenergic-receptor-mediated regulation of ribosomal protein S6 kinases in adult cardiomyocytes

Wang, Lijun, Rolfe, Mark and Proud, Christopher G. (2003) Ca2+-independent protein kinase C activity is required for alpha(1)-adrenergic-receptor-mediated regulation of ribosomal protein S6 kinases in adult cardiomyocytes. Biochemical Journal, 373 (2), 603-611. (doi:10.1042/BJ20030454).

Abstract

The a1-adrenergic agonist, phenylephrine (PE), exerts hypertrophic effects in the myocardium and activates protein synthesis. Both Ca2+-dependent protein kinase C (PKC, PKCa) and Ca2+-independent PKC isoforms (PKCd and e) are detectably expressed in adult rat cardiomyocytes. Stimulation of the a1-adrenergic receptor by PE results in activation of Ca2+-independent PKCs, as demonstrated by translocation of the d 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 PKCd, 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 PKCd or e 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 a1-adrenergic receptor to mTOR signalling and protein synthesis in adult cardiomyocytes.

This record has no associated files available for download.

Contributors

Download statistics