β-adrenergic signaling inhibits Gq-dependent protein kinase D activation by preventing protein Kinase D translocation

C. Blake Nichols, Chia Wei Chang, Maura Ferrero, Brittani M. Wood, Matthew L. Stein, Amanda J. Ferguson, Derrick Ha, Robert R. Rigor, Sven Bossuyt, Julie B C Bossuyt

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Rationale: Both β-adrenergic receptor (β-AR) and Gq-coupled receptor (GqR) agonist-driven signaling play key roles in the events, leading up to and during cardiac dysfunction. How these stimuli interact at the level of protein kinase D (PKD), a nodal point in cardiac hypertrophic signaling, remains unclear. OBJECTIVE:: To assess the spatiotemporal dynamics of PKD activation in response to β-AR signaling alone and on coactivation with GqR-agonists. This will test our hypothesis that compartmentalized PKD signaling reconciles disparate findings of PKA facilitation and inhibition of PKD activation. METHODS AND RESULTS:: We report on the spatial and temporal profiles of PKD activation using green fluorescent protein-tagged PKD (wildtype or mutant S427E) and targeted fluorescence resonance energy transfer-based biosensors (D-kinase activity reporters) in adult cardiomyocytes. We find that β-AR/PKA signaling drives local nuclear activation of PKD, without preceding sarcolemmal translocation. We also discover pronounced interference of β-AR/cAMP/PKA signaling on GqR-induced translocation and activation of PKD throughout the cardiomyocyte. We attribute these effects to direct, PKA-dependent phosphorylation of PKD-S427. We also show that phosphomimetic substitution of S427 likewise impedes GqR-induced PKD translocation and activation. In neonatal myocytes, S427E inhibits GqR-evoked cell growth and expression of hypertrophic markers. Finally, we show altered S427 phosphorylation in transverse aortic constriction-induced hypertrophy. CONCLUSIONS:: β-AR signaling triggers local nuclear signaling and inhibits GqR-mediated PKD activation by preventing its intracellular translocation. PKA-dependent phosphorylation of PKD-S427 fine-tunes the PKD responsiveness to GqR-agonists, serving as a key integration point for β-adrenergic and Gq-coupled stimuli.

Original languageEnglish (US)
Pages (from-to)1398-1409
Number of pages12
JournalCirculation Research
Volume114
Issue number9
DOIs
StatePublished - Apr 25 2014

Keywords

  • adrenergic
  • cardiac
  • Cyclic AMP-dependent protein kinases
  • GTP-binding proteins
  • myocytes
  • protein kinase D
  • receptors

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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    Nichols, C. B., Chang, C. W., Ferrero, M., Wood, B. M., Stein, M. L., Ferguson, A. J., Ha, D., Rigor, R. R., Bossuyt, S., & Bossuyt, J. B. C. (2014). β-adrenergic signaling inhibits Gq-dependent protein kinase D activation by preventing protein Kinase D translocation. Circulation Research, 114(9), 1398-1409. https://doi.org/10.1161/CIRCRESAHA.114.303870