Phosphodiesterase 4B in the cardiac L-type Ca²âº channel complex regulates Ca²âº current and protects against ventricular arrhythmias in mice.

ABSTRACT

ß-Adrenergic receptors (ß-ARs) enhance cardiac contractility by increasing cAMP levels and activating PKA. PKA increases Ca²âº-induced Ca²âº release via phosphorylation of L-type Ca²âº 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 ß-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 ß-AR stimulation of the L-type Ca²âº 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 ß-AR stimulation, Ca²âº transients, cell contraction, and spontaneous Ca²âº 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 ß-AR stimulation and suggest that distinct PDE4 subtypes are important for normal regulation of Ca²âº-induced Ca²âº release in cardiomyocytes.