title: Phosphodiesterase 4D regulates baseline sarcoplasmic reticulum Ca2+ release and cardiac contractility, independently of L-type Ca2+ current.
abstract: BACKGROUND
  Baseline contractility of mouse hearts is modulated in a phosphatidylinositol 3-kinase-γ-dependent manner by type 4 phosphodiesterases (PDE4), which regulate cAMP levels within microdomains containing the sarcoplasmic reticulum (SR) calcium ATPase type 2a (SERCA2a).
  
  
  OBJECTIVE
  The goal of this study was to determine whether PDE4D regulates basal cardiac contractility.
  
  
  RESULTS
  At 10 to 12 weeks of age, baseline cardiac contractility in PDE4D-deficient (PDE4D(-/-)) mice was elevated mice in vivo and in Langendorff perfused hearts, whereas isolated PDE4D(-/-) cardiomyocytes showed increased whole-cell Ca2+ transient amplitudes and SR Ca2+content but unchanged L-type calcium current, compared with littermate controls (WT). The protein kinase A inhibitor R(p)-adenosine-3',5' cyclic monophosphorothioate (R(p)-cAMP) lowered whole-cell Ca2+ transient amplitudes and SR Ca2+ content in PDE4D(-/-) cardiomyocytes to WT levels. The PDE4 inhibitor rolipram had no effect on cardiac contractility, whole-cell Ca2+ transients, or SR Ca2+ content in PDE4D(-/-) preparations but increased these parameters in WT myocardium to levels indistinguishable from those in PDE4D(-/-). The functional changes in PDE4D(-/-) myocardium were associated with increased PLN phosphorylation but not cardiac ryanodine receptor phosphorylation. Rolipram increased PLN phosphorylation in WT cardiomyocytes to levels indistinguishable from those in PDE4D(-/-) cardiomyocytes. In murine and failing human hearts, PDE4D coimmunoprecipitated with SERCA2a but not with cardiac ryanodine receptor.
  
  
  CONCLUSIONS
  PDE4D regulates basal cAMP levels in SR microdomains containing SERCA2a-PLN, but not L-type Ca2+ channels or ryanodine receptor. Because whole-cell Ca2+ transient amplitudes are reduced in failing human myocardium, these observations may have therapeutic implications for patients with heart failure.
authors: Department of Physiology, University of Toronto.|Heart & Stroke Richard Lewar Centre of Excellence, University of Toronto.
authors: Sanja
authors: S
authors: Beca
authors: Department of Physiology, University of Toronto.|Heart & Stroke Richard Lewar Centre of Excellence, University of Toronto.
authors: Peter B
authors: PB
authors: Helli
authors: Department of Physiology, University of Toronto.|Heart & Stroke Richard Lewar Centre of Excellence, University of Toronto.
authors: Jeremy A
authors: JA
authors: Simpson
authors: Department of Physiology, University of Toronto.|Heart & Stroke Richard Lewar Centre of Excellence, University of Toronto.
authors: Dongling
authors: D
authors: Zhao
authors: Department of Physiology, University of Toronto.|Heart & Stroke Richard Lewar Centre of Excellence, University of Toronto.
authors: Gerrie P
authors: GP
authors: Farman
authors: Department of Physiology and Biophysics, University of Calgary.
authors: Peter
authors: P
authors: Jones
authors: Department of Physiology and Biophysics, University of Calgary.
authors: Xixi
authors: X
authors: Tian
authors: Department of Pathology and Molecular Medicine, Queen's University, Kingston.
authors: Lindsay S
authors: LS
authors: Wilson
authors: The Cardiovascular Pulmonary Branch, National Heart, Lung and Blood Institute, NIH, Bethesda.
authors: Faiyaz
authors: F
authors: Ahmad
authors: Department of Physiology and Biophysics, University of Calgary.
authors: S R Wayne
authors: SRW
authors: Chen
authors: VA Salt Lake City Health Care System and Departments of Internal Medicine (Cardiology) and Pharmacology, University of Utah.
authors: Matthew A
authors: MA
authors: Movsesian
authors: The Cardiovascular Pulmonary Branch, National Heart, Lung and Blood Institute, NIH, Bethesda.
authors: Vincent
authors: V
authors: Manganiello
authors: Department of Pathology and Molecular Medicine, Queen's University, Kingston.|Department of Pharmacology and Toxicology, Queen's University, Kingston.
authors: Donald H
authors: DH
authors: Maurice
authors: Department of Obstetrics and Gynaecology, University of California San Francisco.
authors: Marco
authors: M
authors: Conti
authors: Department of Physiology, University of Toronto.|Department of Medicine, University of Toronto.|Division of Cardiology at the University Health Network, University of Toronto.|Heart & Stroke Richard Lewar Centre of Excellence, University of Toronto.
authors: Peter H
authors: PH
authors: Backx
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000502:physiology*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000378:metabolism / Q000473:pathology; D000242:Cyclic AMP / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D009200:Myocardial Contraction / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D000099211:Phospholamban
chemical_list: D002118:Calcium; D020746:Calcium Channels, L-Type; D002135:Calcium-Binding Proteins; D000242:Cyclic AMP; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D019869:Phosphatidylinositol 3-Kinases; D019837:Ryanodine Receptor Calcium Release Channel; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000099211:Phospholamban; C506946:ATP2A2 protein, human; C506947:Atp2a2 protein, mouse