ArticleEuropean heart journal2023
Phosphodiesterase 8 governs cAMP/PKA-dependent reduction of L-type calcium current in human atrial fibrillation: a novel arrhythmogenic mechanism.
Article in European heart journal, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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33 citing papers in PubMed, 43 citations in OpenAlex.
- Multiple 4q25 risk variants impair calcium homeostasis and compromise left atrial function.Cardiovascular research · 2026Article
- Downregulation of L-type CaHeart rhythm · 2026Article
- Identification and validation of five hypoxia- and immune-related hub targets in atrial fibrillation.Journal of cardiothoracic surgery · 2026Article
- Models of the human heart for biomedical research: Opportunities and challenges.Physiological reports · 2026Review
- 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
- Arrhythmia-induced cardiomyopathy: focus on atrial fibrillation.Nature reviews. Cardiology · 2026Review
- Cyclic AMP-dependent regulation of ryanodine receptors in healthy and diseased hearts.Journal of molecular and cellular cardiology · 2026Review
- Atrial cardiomyopathy: From healthy atria to atrial failure. A clinical consensus statement of the Heart Failure Association of the ESC.European journal of heart failure · 2025Article
- Arrhythmia-Induced Cardiomyopathy in Atrial Fibrillation: Pathogenesis, Diagnosis, and Treatment.Life (Basel, Switzerland) · 2025Review
- Electrophysiological Mechanisms and Therapeutic Potential of Calcium Channels in Atrial Fibrillation.Reviews in cardiovascular medicine · 2025Review
- Disease mechanism and novel drug therapies for atrial fibrillation.Medizinische Genetik : Mitteilungsblatt des Berufsverbandes Medizinische Genetik e.V · 2025Article
- Cognitive improvement effects of PF-04957325, a phosphodiesterase-8 inhibitor, in mouse models of Alzheimer's disease via modulating neuroinflammation.The international journal of neuropsychopharmacology · 2025Article
- Cyclic nucleotide phosphodiesterases as drug targets.Pharmacological reviews · 2025Review
- Nanodomain cAMP signaling in cardiac pathophysiology: potential for developing targeted therapeutic interventions.Physiological reviews · 2025Review
- Review
- Takeda G protein-coupled receptor 5 (TGR5): an attractive therapeutic target for aging-related cardiovascular diseases.Frontiers in pharmacology · 2025Review
- An oxidative stress-related molecular signature in atherosclerosis: identification of risk genes, construction of a diagnostic model, and characterization of immunocyte landscape.Frontiers in cardiovascular medicine · 2025Article
- Phosphodiesterases: Evolving Concepts and Implications for Human Therapeutics.Annual review of pharmacology and toxicology · 2025Review
- Altered Protein Kinase A-Dependent Phosphorylation of Cav1.2 in Left Ventricular Myocardium fromInternational journal of molecular sciences · 2024Article
- Impact of Overnight Storage of Human Atrial Myocytes on Intracellular Calcium Homeostasis and Electrophysiological Utility.Biomolecules · 2024Article
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17 authors at 8 institutions in 5 countries.
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Abstract
aimsAtrial fibrillation (AF) is associated with altered cAMP/PKA signaling and an AF-promoting reduction of L-type Ca2+-current (ICa,L), the mechanisms of which are poorly understood. Cyclic-nucleotide phosphodiesterases (PDEs) degrade cAMP and regulate PKA-dependent phosphorylation of key calcium-handling proteins, including the ICa,L-carrying Cav1.2α1C subunit. The aim was to assess whether altered function of PDE type-8 (PDE8) isoforms contributes to the reduction of ICa,L in persistent (chronic) AF (cAF) patients. METHODS AND
resultsmRNA, protein levels, and localization of PDE8A and PDE8B isoforms were measured by RT-qPCR, western blot, co-immunoprecipitation and immunofluorescence. PDE8 function was assessed by FRET, patch-clamp and sharp-electrode recordings. PDE8A gene and protein levels were higher in paroxysmal AF (pAF) vs. sinus rhythm (SR) patients, whereas PDE8B was upregulated in cAF only. Cytosolic abundance of PDE8A was higher in atrial pAF myocytes, whereas PDE8B tended to be more abundant at the plasmalemma in cAF myocytes. In co-immunoprecipitation, only PDE8B2 showed binding to Cav1.2α1C subunit which was strongly increased in cAF. Accordingly, Cav1.2α1C showed a lower phosphorylation at Ser1928 in association with decreased ICa,L in cAF. Selective PDE8 inhibition increased Ser1928 phosphorylation of Cav1.2α1C, enhanced cAMP at the subsarcolemma and rescued the lower ICa,L in cAF, which was accompanied by a prolongation of action potential duration at 50% of repolarization.
conclusionBoth PDE8A and PDE8B are expressed in human heart. Upregulation of PDE8B isoforms in cAF reduces ICa,L via direct interaction of PDE8B2 with the Cav1.2α1C subunit. Thus, upregulated PDE8B2 might serve as a novel molecular mechanism of the proarrhythmic reduction of ICa,L in cAF.
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