دورية أكاديمية
Phosphodiesterase 8 governs cAMP/PKA-dependent reduction of L-type calcium current in human atrial fibrillation: a novel arrhythmogenic mechanism
| العنوان: | Phosphodiesterase 8 governs cAMP/PKA-dependent reduction of L-type calcium current in human atrial fibrillation: a novel arrhythmogenic mechanism |
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| المؤلفون: | Pavlidou, Nefeli, Grammatika, Dobrev, Shokoufeh, Beneke, Kira, Reinhardt, Franziska, Pecha, Simon, Jacquet, Eric, Abu-Taha, Issam, H, Schmidt, Constanze, Voigt, Niels, Kamler, Markus, Schnabel, Renate, B, Baczkó, Istvan, Garnier, Anne, Reichenspurner, Hermann, Nikolaev, Viacheslav, O, Dobrev, Dobromir, Molina, Cristina, E |
| المساهمون: | Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf Hamburg (UKE), German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), University Heart Center Hamburg, Universität Duisburg-Essen = University of Duisburg-Essen Essen, Université de Montréal (UdeM), Baylor College of Medicine (BCM), Baylor University, Centre de recherches en psychopathologie et psychologie clinique (CRPPC), Université Lumière - Lyon 2 (UL2), University Medical Center Heidelberg, University Medical Center Göttingen (UMG), University of Szeged Szeged, Signalisation et physiopathologie cardiovasculaire (CARPAT (UMRS1180)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay |
| المصدر: | ISSN: 0195-668X. |
| بيانات النشر: | HAL CCSD Oxford University Press (OUP) |
| سنة النشر: | 2023 |
| المجموعة: | Portail HAL de l'Université Lumière Lyon 2 |
| مصطلحات موضوعية: | Atrial fibrillation, Calcium handling, ICa, PDE8, Phosphodiesterases, cAMP, [SDV]Life Sciences [q-bio] |
| الوصف: | International audience ; Aims: Atrial 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 results: mRNA, 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.Conclusion: Both 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| العلاقة: | info:eu-repo/semantics/altIdentifier/pmid/36810794; inserm-04410849; https://inserm.hal.science/inserm-04410849Test; https://inserm.hal.science/inserm-04410849/documentTest; https://inserm.hal.science/inserm-04410849/file/Pavlidou%20Garnier%2023.pdfTest; PUBMED: 36810794; PUBMEDCENTRAL: PMC10344654 |
| DOI: | 10.1093/eurheartj/ehad086 |
| الإتاحة: | https://doi.org/10.1093/eurheartj/ehad086Test https://inserm.hal.science/inserm-04410849Test https://inserm.hal.science/inserm-04410849/documentTest https://inserm.hal.science/inserm-04410849/file/Pavlidou%20Garnier%2023.pdfTest |
| حقوق: | info:eu-repo/semantics/OpenAccess |
| رقم الانضمام: | edsbas.A55F8D7C |
| قاعدة البيانات: | BASE |
| DOI: | 10.1093/eurheartj/ehad086 |
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