Spatiotemporally distinct protein kinase D activation in adult cardiomyocytes in response to phenylephrine and endothelin

Julie B C Bossuyt, Chia Wei Chang, Kathryn Helmstadter, Maya T. Kunkel, Alexandra C. Newton, Kenneth S. Campbell, Jody L. Martin, Sven Bossuyt, Seth L. Robia, Donald M Bers

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

Protein kinase D (PKD) is a nodal point in cardiac hypertrophic signaling. It triggers nuclear export of class II histone deacetylase (HDAC) and regulates transcription. Although this pathway is thought to be critical in cardiac hypertrophy and heart failure, little is known about spatiotemporal aspects of PKD activation at the myocyte level. Here, we demonstrate that in adult cardiomyocytes two important neurohumoral stimuli that induce hypertrophy, endothelin-1 (ET1) and phenylephrine (PE), trigger comparable global PKD activation and HDAC5 nuclear export, but via divergent spatiotemporal PKD signals. PE-induced HDAC5 export is entirely PKD-dependent, involving fleeting sarcolemmal PKD translocation (for activation) and very rapid subsequent nuclear import. In contrast, ET1 recruits and activates PKD that remains predominantly sarcolemmal. This explains why PE-induced nuclear HDAC5 export in myocytes is totally PKD-dependent, whereas ET1-induced HDAC5 export depends more prominently on InsP3 and CaMKII signaling. Thus α-adrenergic and ET-1 receptor signaling via PKD in adult myocytes feature dramatic differences in cellular localization and translocation in mediating hypertrophic signaling. This raises new opportunities for targeted therapeutic intervention into distinct limbs of this hypertrophic signaling pathway.

Original languageEnglish (US)
Pages (from-to)33390-33400
Number of pages11
JournalJournal of Biological Chemistry
Volume286
Issue number38
DOIs
StatePublished - Sep 23 2011

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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    Bossuyt, J. B. C., Chang, C. W., Helmstadter, K., Kunkel, M. T., Newton, A. C., Campbell, K. S., Martin, J. L., Bossuyt, S., Robia, S. L., & Bers, D. M. (2011). Spatiotemporally distinct protein kinase D activation in adult cardiomyocytes in response to phenylephrine and endothelin. Journal of Biological Chemistry, 286(38), 33390-33400. https://doi.org/10.1074/jbc.M111.246447