Phosphodiesterase 8A (PDE8A) regulates excitation-contraction coupling in ventricular myocytes.
In ventricular myocytes, activation of protein kinase A (PKA) by 3'-5' cyclic adenosine monophosphate (cAMP) increases the force of contraction by increasing L-type Ca(2+) channel currents (I(Ca)) and sarcoplasmic reticulum (SR) Ca(2+) release during excitation-contraction coupling. Cyclic-nucleotide phosphodiesterases (PDEs) comprise a large family of enzymes whose role in the cell is to regulate the spatial and temporal profile of cAMP signals by controlling the degradation of this second messenger. At present, however, the molecular identity and functional roles of the PDEs expressed in ventricular myocytes are incompletely understood. Here, we tested the hypothesis that PDE8A plays a critical role in the modulation of at least one compartment of cAMP and hence PKA activity during beta-adrenergic receptor (betaAR) activation in ventricular myocytes. Consistent with this hypothesis, we found that PDE8A transcript and protein are expressed in ventricular myocytes. Our data indicate that evoked [Ca(2+)](i) transients and I(Ca) increased to a much larger extent in PDE8A null (PDE8A(-/-)) than in wild-type (WT) myocytes during beta-adrenergic signaling activation. In addition, Ca(2+) spark activity was higher in PDE8A(-/-) than in WT myocytes. Our data indicate that PDE8A is a novel cardiac PDE that controls one or more pools of cAMP implicated in regulation of Ca(2+) movement through cardiomyocyte.
Patrucco
Enrico
E
Department of Pharmacology, University of Washington, School of Medicine, Seattle, WA 98195, USA. enripat@u.washington
Albergine
Masami Shimizu
MS
Santana
Luis F
LF
Beavo
Joseph A
JA
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism*; D000818:Animals; D056966:Excitation Contraction Coupling / Q000187:drug effects; D006352:Heart Ventricles / Q000166:cytology*; D015640:Ion Channel Gating / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D009206:Myocardium / Q000201:enzymology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology*; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism
D015105:3',5'-Cyclic-AMP Phosphodiesterases; C520790:Pde8a protein, mouse; D007545:Isoproterenol