Phosphodiesterase 4B in the cardiac L-type Ca2+ channel complex regulates Ca2+ current and protects against ventricular arrhythmias in mice
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
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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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 1

PDE4 modulates β-AR stimulation of ICa,L in mouse ventricular myocytes.

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PDE4 modulates β-AR stimulation of ICa,L in mouse ventricular myocytes. ...
(A) Typical time course of ICa,L amplitude in a cell stimulated by a 15-second pulse of Iso (100 nM). Each square represents the amplitude of ICa,L recorded every 8 seconds during a depolarization from –50 to 0 mV. (B) ICa,L was further increased when the cell was preincubated with the PDE4 inhibitor Ro 20-1724 (Ro; 10 μM) 2 minutes prior to the 15-second pulse of Iso (100 nM) and maintained throughout the experiment. The individual current traces shown on top of A and B were recorded at the times indicated by the corresponding roman numerals in the graphs below. (C) Mean variation of ICa,L after Iso (100 nM, 15 seconds) application alone (black diamonds; n = 62 myocytes) or when PDE4 was inhibited by Ro 20-1724 (gray squares; n = 37 myocytes). All curves represent the mean ± SEM. *P < 0.05 indicates the first of the statistically significant points on the graph. All points that occur after this time point are significant.