| First Author | Nichols CB | Year | 2014 |
| Journal | Circ Res | Volume | 114 |
| Issue | 9 | Pages | 1398-409 |
| PubMed ID | 24643961 | Mgi Jnum | J:246861 |
| Mgi Id | MGI:5921118 | Doi | 10.1161/CIRCRESAHA.114.303870 |
| Citation | Nichols CB, et al. (2014) beta-adrenergic signaling inhibits Gq-dependent protein kinase D activation by preventing protein kinase D translocation. Circ Res 114(9):1398-409 |
| abstractText | RATIONALE: Both beta-adrenergic receptor (beta-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 beta-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 beta-AR/PKA signaling drives local nuclear activation of PKD, without preceding sarcolemmal translocation. We also discover pronounced interference of beta-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: beta-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 beta-adrenergic and Gq-coupled stimuli. |
