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Phosphodiesterase 4B in the cardiac L-type Ca2+ channel complex regulates Ca2+ current and protects against ventricular arrhythmias in mice

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dc.contributor.author Abi-Gerges, Aniella
dc.contributor.author Mika, Delphine
dc.contributor.author Richter, Wito
dc.contributor.author Leroy, Jerome
dc.contributor.author Charpentier, Flavien
dc.contributor.author Mateo, Philippe
dc.date.accessioned 2017-10-19T12:18:09Z
dc.date.available 2017-10-19T12:18:09Z
dc.date.copyright 2011 en_US
dc.identifier.issn 1558-8238 en_US
dc.identifier.uri http://hdl.handle.net/10725/6359
dc.description.abstract β-Adrenergic receptors (β-ARs) enhance cardiac contractility by increasing cAMP levels and activating PKA. PKA increases Ca2+-induced Ca2+ release via phosphorylation of L-type Ca2+ channels (LTCCs) and ryanodine receptor 2. Multiple cyclic nucleotide phosphodiesterases (PDEs) regulate local cAMP concentration in cardiomyocytes, with PDE4 being predominant for the control of β-AR–dependent cAMP signals. Three genes encoding PDE4 are expressed in mouse heart: Pde4a, Pde4b, and Pde4d. Here we show that both PDE4B and PDE4D are tethered to the LTCC in the mouse heart but that β-AR stimulation of the L-type Ca2+ current (ICa,L) is increased only in Pde4b–/– mice. A fraction of PDE4B colocalized with the LTCC along T-tubules in the mouse heart. Under β-AR stimulation, Ca2+ transients, cell contraction, and spontaneous Ca2+ release events were increased in Pde4b–/– and Pde4d–/– myocytes compared with those in WT myocytes. In vivo, after intraperitoneal injection of isoprenaline, catheter-mediated burst pacing triggered ventricular tachycardia in Pde4b–/– mice but not in WT mice. These results identify PDE4B in the CaV1.2 complex as a critical regulator of ICa,L during β-AR stimulation and suggest that distinct PDE4 subtypes are important for normal regulation of Ca2+-induced Ca2+ release in cardiomyocytes. en_US
dc.language.iso en en_US
dc.title Phosphodiesterase 4B in the cardiac L-type Ca2+ channel complex regulates Ca2+ current and protects against ventricular arrhythmias in mice en_US
dc.type Article en_US
dc.description.version Published en_US
dc.author.school SOM en_US
dc.author.idnumber 201402416 en_US
dc.author.department N/A en_US
dc.description.embargo N/A en_US
dc.relation.journal Journal of Clinical Investigation en_US
dc.journal.volume 12 en_US
dc.journal.issue 7 en_US
dc.article.pages 2651-2661 en_US
dc.identifier.doi http://dx.doi.org/10.1172/JCI44747 en_US
dc.identifier.ctation Leroy, J., Richter, W., Mika, D., Castro, L. R., Abi-Gerges, A., Xie, M., ... & Westenbroek, R. (2011). Phosphodiesterase 4B in the cardiac L-type Ca2+ channel complex regulates Ca2+ current and protects against ventricular arrhythmias in mice. The Journal of clinical investigation, 121(7), 2651. en_US
dc.author.email aniella.abigerges@lau.edu.lb en_US
dc.identifier.tou http://libraries.lau.edu.lb/research/laur/terms-of-use/articles.php en_US
dc.identifier.url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3223827/ en_US
dc.author.affiliation Lebanese American University en_US


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