Pde4b gene knockout in mice significantly increased L-type Ca2+ current potentiation upon beta-adrenergic stimulation (78.3% vs 58.8% in WT, p<0.001), promoting ventricular tachycardia.
Does PDE4B ablation increase L-type Ca2+ current and susceptibility to ventricular arrhythmias during beta-adrenergic stimulation in mice?
PDE4B is a critical regulator of the L-type Ca2+ channel complex during beta-adrenergic stimulation, and its absence increases susceptibility to ventricular arrhythmias.
Absolute Event Rate: 78.3% vs 58.8%
p-value: p=<0.001
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.
Leroy et al. (Mon,) conducted a other in Ventricular Arrhythmias. Pde4b gene knockout vs. Wild-type (WT) mice was evaluated on Maximal L-type Ca2+ current (ICa,L) potentiation by isoprenaline (p=<0.001). Pde4b gene knockout in mice significantly increased L-type Ca2+ current potentiation upon beta-adrenergic stimulation (78.3% vs 58.8% in WT, p<0.001), promoting ventricular tachycardia.