title: Spatiotemporally distinct protein kinase D activation in adult cardiomyocytes in response to phenylephrine and endothelin.
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 InsP(3) 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.
authors.affiliation: Department of Pharmacology, University of California, Davis, California 95616, USA. jbossuyt@ucdavis.edu
authors.forename: Julie
authors.initials: J
authors.lastname: Bossuyt
authors.forename: Chia-Wei
authors.initials: CW
authors.lastname: Chang
authors.forename: Kathryn
authors.initials: K
authors.lastname: Helmstadter
authors.forename: Maya T
authors.initials: MT
authors.lastname: Kunkel
authors.forename: Alexandra C
authors.initials: AC
authors.lastname: Newton
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Campbell
authors.forename: Jody L
authors.initials: JL
authors.lastname: Martin
authors.forename: Sven
authors.initials: S
authors.lastname: Bossuyt
authors.forename: Seth L
authors.initials: SL
authors.lastname: Robia
authors.forename: Donald M
authors.initials: DM
authors.lastname: Bers
mesh_terms: D000375:Aging / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D019332:Endothelin-1 / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D036681:Fluorescence Recovery After Photobleaching; D049452:Green Fluorescent Proteins; D006655:Histone Deacetylases / Q000378:metabolism; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D010656:Phenylephrine / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D011817:Rabbits; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012508:Sarcolemma / Q000187:drug effects / Q000201:enzymology; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: D019332:Endothelin-1; D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins; D010656:Phenylephrine; C089212:protein kinase D; D011493:Protein Kinase C; D006655:Histone Deacetylases