| First Author | Leroy J | Year | 2011 |
| Journal | J Clin Invest | Volume | 121 |
| Issue | 7 | Pages | 2651-61 |
| PubMed ID | 21670503 | Mgi Jnum | J:175643 |
| Mgi Id | MGI:5286798 | Doi | 10.1172/JCI44747 |
| Citation | Leroy J, et al. (2011) Phosphodiesterase 4B in the cardiac L-type Ca(2) channel complex regulates Ca(2) current and protects against ventricular arrhythmias in mice. J Clin Invest 121(7):2651-61 |
| abstractText | beta-Adrenergic receptors (beta-ARs) enhance cardiac contractility by increasing cAMP levels and activating PKA. PKA increases Ca(2)-induced Ca(2) release via phosphorylation of L-type Ca(2) 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 Ca(2) 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 beta-AR stimulation, Ca(2) transients, cell contraction, and spontaneous Ca(2) 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 beta-AR stimulation and suggest that distinct PDE4 subtypes are important for normal regulation of Ca(2)-induced Ca(2) release in cardiomyocytes. |
