Document Detail


Phosphodiesterase 4D regulates baseline sarcoplasmic reticulum Ca2+ release and cardiac contractility, independently of L-type Ca2+ current.
MedLine Citation:
PMID:  21903937     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
RATIONALE: 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.
METHODS AND 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:
Sanja Beca; Peter B Helli; Jeremy A Simpson; Dongling Zhao; Gerrie P Farman; Peter P Jones; Xixi Tian; Lindsay S Wilson; Faiyaz Ahmad; S R Wayne Chen; Matthew A Movsesian; Vincent Manganiello; Donald H Maurice; Marco Conti; Peter H Backx
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2011-09-08
Journal Detail:
Title:  Circulation research     Volume:  109     ISSN:  1524-4571     ISO Abbreviation:  Circ. Res.     Publication Date:  2011 Oct 
Date Detail:
Created Date:  2011-10-14     Completed Date:  2011-12-12     Revised Date:  2014-08-21    
Medline Journal Info:
Nlm Unique ID:  0047103     Medline TA:  Circ Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1024-30     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Calcium / metabolism*
Calcium Channels, L-Type / physiology*
Calcium-Binding Proteins / metabolism
Cardiomyopathy, Dilated / metabolism,  pathology
Cyclic AMP / metabolism
Cyclic Nucleotide Phosphodiesterases, Type 4 / genetics,  metabolism*
Female
Heart Ventricles / metabolism,  pathology
Humans
Male
Mice
Mice, Knockout
Models, Animal
Myocardial Contraction / physiology*
Myocytes, Cardiac / metabolism*,  pathology
Phosphatidylinositol 3-Kinases / metabolism
Ryanodine Receptor Calcium Release Channel / metabolism
Sarcoplasmic Reticulum / metabolism*
Sarcoplasmic Reticulum Calcium-Transporting ATPases / metabolism
Grant Support
ID/Acronym/Agency:
HL0927088/HL/NHLBI NIH HHS; R01 HL092788/HL/NHLBI NIH HHS; ZIA HL002540-19/HL/NHLBI NIH HHS; //Canadian Institutes of Health Research
Chemical
Reg. No./Substance:
0/Calcium Channels, L-Type; 0/Calcium-Binding Proteins; 0/Ryanodine Receptor Calcium Release Channel; 0/phospholamban; E0399OZS9N/Cyclic AMP; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC 3.1.4.17/Cyclic Nucleotide Phosphodiesterases, Type 4; EC 3.6.3.8/ATP2A2 protein, human; EC 3.6.3.8/Atp2a2 protein, mouse; EC 3.6.3.8/Sarcoplasmic Reticulum Calcium-Transporting ATPases; SY7Q814VUP/Calcium
Comments/Corrections

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