title: 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.affiliation: INSERM UMR-S 769, Châtenay-Malabry, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Leroy
authors.forename: Wito
authors.initials: W
authors.lastname: Richter
authors.forename: Delphine
authors.initials: D
authors.lastname: Mika
authors.forename: Liliana R V
authors.initials: LR
authors.lastname: Castro
authors.forename: Aniella
authors.initials: A
authors.lastname: Abi-Gerges
authors.forename: Moses
authors.initials: M
authors.lastname: Xie
authors.forename: Colleen
authors.initials: C
authors.lastname: Scheitrum
authors.forename: Florence
authors.initials: F
authors.lastname: Lefebvre
authors.forename: Julia
authors.initials: J
authors.lastname: Schittl
authors.forename: Philippe
authors.initials: P
authors.lastname: Mateo
authors.forename: Ruth
authors.initials: R
authors.lastname: Westenbroek
authors.forename: William A
authors.initials: WA
authors.lastname: Catterall
authors.forename: Flavien
authors.initials: F
authors.lastname: Charpentier
authors.forename: Marco
authors.initials: M
authors.lastname: Conti
authors.forename: Rodolphe
authors.initials: R
authors.lastname: Fischmeister
authors.forename: Grégoire
authors.initials: G
authors.lastname: Vandecasteele
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000503:physiopathology*; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000235:genetics / Q000378:metabolism*; D006352:Heart Ventricles / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000502:physiology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology*; D018408:Patch-Clamp Techniques; D011943:Receptors, Adrenergic, beta / Q000378:metabolism
chemical_list: C514350:CACNA1C protein, mouse; D020746:Calcium Channels, L-Type; D007527:Isoenzymes; D011943:Receptors, Adrenergic, beta; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C543000:PDE4B protein, mouse; C531980:PDE4D protein, mouse; D002118:Calcium