Phosphodiesterase 4B in the cardiac L-type Ca²⁺ channel complex regulates Ca²⁺ current and protects against ventricular arrhythmias in mice.
Copyright policy )Phosphodiesterase 4B in the cardiac L-type Ca²⁺ channel complex regulates Ca²⁺ current and protects against ventricular arrhythmias in mice.
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.
Male, Mice, Knockout, Patch-Clamp Techniques, Calcium Channels, L-Type, Heart Ventricles, Arrhythmias, Cardiac, Myocardial Contraction, Cyclic Nucleotide Phosphodiesterases, Type 4, Isoenzymes, Mice, Inbred C57BL, Mice, Receptors, Adrenergic, beta, Animals, Humans, Calcium, Myocytes, Cardiac
Male, Mice, Knockout, Patch-Clamp Techniques, Calcium Channels, L-Type, Heart Ventricles, Arrhythmias, Cardiac, Myocardial Contraction, Cyclic Nucleotide Phosphodiesterases, Type 4, Isoenzymes, Mice, Inbred C57BL, Mice, Receptors, Adrenergic, beta, Animals, Humans, Calcium, Myocytes, Cardiac
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