Phosphodiesterase 4B in the cardiac L-type Ca2+ channel complex regulates Ca2+ current and protects against ventricular arrhythmias in mice
Jérôme Leroy, … , Rodolphe Fischmeister, Grégoire Vandecasteele
Jérôme Leroy, … , Rodolphe Fischmeister, Grégoire Vandecasteele
Published June 13, 2011
Citation Information: J Clin Invest. 2011;121(7):2651-2661. https://doi.org/10.1172/JCI44747.
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Research Article Cardiology

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

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.

Authors

Jérôme Leroy, Wito Richter, Delphine Mika, Liliana R.V. Castro, Aniella Abi-Gerges, Moses Xie, Colleen Scheitrum, Florence Lefebvre, Julia Schittl, Philippe Mateo, Ruth Westenbroek, William A. Catterall, Flavien Charpentier, Marco Conti, Rodolphe Fischmeister, Grégoire Vandecasteele

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Figure 3

PDE4B and PDE4D are part of the LTCC complex.

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PDE4B and PDE4D are part of the LTCC complex. (A) CaV1.2 was immunopreci...
(A) CaV1.2 was immunoprecipitated from cardiac homogenates of WT mice, Pde4a–/–, Pde4b–/–, and Pde4d–/– mice. The associated PDE4 activity was assessed using rolipram. **P < 0.01. (B) PDE4B was detected in cardiac lysates from WT animals and coimmunoprecipitated with CaV1.2. (C) PDE4D was also detected in cardiac lysates from WT animals and was associated with CaV1.2. IP IgG, negative control. Data are representative of at least 3 independent experiments.