ArticleCirculation research2011
Phosphodiesterase 4D regulates baseline sarcoplasmic reticulum Ca2+ release and cardiac contractility, independently of L-type Ca2+ current.
Article in Circulation research, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers.
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Who cites it
57 citing papers in PubMed, 106 citations in OpenAlex.
- Troponin: biology, molecular mechanisms, and multidimensional clinical applications.Molecular biomedicine · 2026Review
- Multitarget Strategy for Treatment of Pulmonary Arterial Hypertension: Combination of Mesenchymal Cells with Novel PDE-4 Inhibitor.Pharmaceuticals (Basel, Switzerland) · 2026Article
- Phosphodiesterase 8 regulation of excitation-contraction coupling as a target for cardiovascular disease: is it my turn now?American journal of physiology. Heart and circulatory physiology · 2026Review
- Reawakening cAMP signalling in cancer cachexia.Nature metabolism · 2025Article
- Calcium handling remodeling in dilated cardiomyopathy: From molecular mechanisms to targeted therapies.Channels (Austin, Tex.) · 2025Review
- Do Glioma Cells Rewire Neural Circuits through Epigenetic Changes? DNA Methylation Analysis of Genes Involved in Neuron-Glioma Communication in the Human Frontal Cortex.Journal of molecular neuroscience : MN · 2025Article
- The toxicological impact of PET-MPs exposure on atherosclerosis: insights from network toxicology, molecular docking, and machine learning.Scientific reports · 2025Article
- Autonomic imbalance in cardiovascular disease: molecular mechanisms and emerging therapeutics.American journal of physiology. Cell physiology · 2025Review
- Nanodomain cAMP signaling in cardiac pathophysiology: potential for developing targeted therapeutic interventions.Physiological reviews · 2025Review
- Review
- Essential Role of the RIα Subunit of cAMP-Dependent Protein Kinase in Regulating Cardiac Contractility and Heart Failure Development.Circulation · 2024Article
- Abnormal phosphorylation / dephosphorylation and CaHeart failure reviews · 2024Review
- Differential Downregulation of βJournal of the American Heart Association · 2024Article
- Phosphodiesterase in heart and vessels: from physiology to diseases.Physiological reviews · 2024Review
- Remodelling of cAMP dynamics within the SERCA2a microdomain in heart failure with preserved ejection fraction caused by obesity and type 2 diabetes.Cardiovascular research · 2024Article
- Article
- Low-intensity exercise training improves systolic function of heart during metastatic melanoma-induced cachexia in mice.Heliyon · 2024Article
- Regulation of cardiac function by cAMP nanodomains.Bioscience reports · 2023Review
- A-Kinase Anchoring Proteins in Cardiac Myocytes and Their Roles in Regulating Calcium Cycling.Cells · 2023Review
- Role of CaArchives of toxicology · 2023Review
Corrections and comments
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Authors and funding
15 authors at 5 institutions in 2 countries.
Funding
Abstract
rationaleBaseline 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).
objectiveThe goal of this study was to determine whether PDE4D regulates basal cardiac contractility. METHODS AND
resultsAt 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.
conclusionsPDE4D 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.
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