Phosphodiesterase 4B in the cardiac L-type Ca2+ channel complex regulates Ca2+ 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 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 (I-Ca,I-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 Ca(v)1.2 complex as a critical regulator of I-Ca,I-L during beta-AR stimulation and suggest that distinct PDE4 subtypes are important for normal regulation of Ca2+-induced Ca2+ release in cardiomyocytes.