Phosphodiesterase 4B in the cardiac L-type Ca^sup 2+^ channel complex regulates Ca^sup 2+^ current and protects against ventricular arrhythmias in mice

[beta]-Adrenergic receptors ([beta]-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...

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Bibliographic Details
Published in:The Journal of clinical investigation 2011-07, Vol.121 (7), p.2651
Main Authors: Leroy, Jérôme, Richter, Wito, Mika, Delphine, Castro, Liliana R V, Abi-Gerges, Aniella, Xie, Moses, Scheitrum, Colleen, Lefebvre, Florence, Schitti, Julia, Mateo, Philippe, Westenbroek, Ruth, Catterall, William A, Charpentier, Flavien, Conti, Marco, Fischmeister, Rodolphe, Vandecasteele, Grégoire
Format: Article
Language:English
Subjects:
Adrenergic receptors
Biomedical research
Cardiac arrhythmia
Cardiomyocytes
Catheters
Genes
Heart
Kinases
Phosphorylation
Proteins
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Summary:[beta]-Adrenergic receptors ([beta]-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 [beta]-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 [beta]-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 [beta]-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 [beta]-AR stimulation and suggest that distinct PDE4 subtypes are important for normal regulation of Ca²-induced Ca² release in cardiomyocytes.
ISSN:0021-9738
1558-8238