title: β-Adrenergic receptor stimulation and activation of protein kinase A protect against α1-adrenergic-mediated phosphorylation of protein kinase D and histone deacetylase 5.
abstract: BACKGROUND
  Chronic activation of β(1)-adrenergic receptor (β(1)-AR) signaling can have deleterious effects on the heart, and animal models overexpressing β(1)-ARs develop a dilated cardiomyopathy and heart failure. In the classic β-AR pathway, receptor occupancy by an agonist results in increased cyclic adenosine monophosphate (cAMP) levels and activation of protein kinase A (PKA). However, the role of PKA-dependent signaling in the development and progression of cardiomyopathies and heart failure is controversial, because β-AR signal transduction is generally desensitized in the failing heart and PKA activity is not increased.
  
  
  RESULTS
  Neonatal rat ventricular myocytes were acutely (15 minutes) or chronically (48 hours) treated with isoproterenol, and phosphorylation of protein kinase D (PKD) and histone deacetylase 5 (HDAC5) was measured. Acute β(1)-AR stimulation or expression of constitutively active (CA) PKA reduced α(1)-adrenergic-mediated phosphorylation of HDAC5 and PKD by activation of a phosphatase. Overexpression of CA-PKA also reduced α(1)-adrenergic-mediated increased expression of contractile protein fetal isoforms and promoted repression of adult isoforms, but had no effect on α(1)-adrenergic-mediated cellular hypertrophy.
  
  
  CONCLUSIONS
  These data indicate that the PKA-dependent arm of β-AR signaling can be antihypertrophic and presumably beneficial, through dephosphorylation of PKD and HDAC5 and reduction of hypertrophic fetal isoform gene expression.
authors.affiliation: Division of Cardiology, School of Medicine, University of Colorado Denver, Health Sciences Center Campus, Aurora, Colorado 80045, USA. kika.sucharov@ucdenver.edu
authors.forename: Carmen C
authors.initials: CC
authors.lastname: Sucharov
authors.forename: Karen
authors.initials: K
authors.lastname: Dockstader
authors.forename: Karin
authors.initials: K
authors.lastname: Nunley
authors.forename: Timothy A
authors.initials: TA
authors.lastname: McKinsey
authors.forename: Michael
authors.initials: M
authors.lastname: Bristow
mesh_terms: D058665:Adrenergic beta-1 Receptor Agonists / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D002316:Cardiotonic Agents / Q000494:pharmacology; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D006655:Histone Deacetylases / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000502:physiology*
chemical_list: D058665:Adrenergic beta-1 Receptor Agonists; D002316:Cardiotonic Agents; D018340:Receptors, Adrenergic, alpha-1; C089212:protein kinase D; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; C498619:Hdac5 protein, rat; D006655:Histone Deacetylases