PI3Kγ Is Required for PDE4, not PDE3, Activity in Subcellular Microdomains Containing the Sarcoplasmic Reticular Calcium ATPase in Cardiomyocytes

• Published in: Circulation research 2007-08, Vol.101 (4), p.400-408
• Main Authors: Kerfant, Benoit-Gilles, Zhao, Dongling, Lorenzen-Schmidt, Ilka, Wilson, Lindsay S, Cai, Shitian, Chen, S R. Wayne, Maurice, Donald H, Backx, Peter H
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Fundamental and applied biological sciences. Psychology; Vertebrates: cardiovascular system
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/CIRCRESAHA.107.156422

We recently showed that phosphoinositide-3-kinase-γ–deficient (PI3Kγ) mice have enhanced cardiac contractility attributable to cAMP-dependent increases in sarcoplasmic reticulum (SR) Ca content and release but not L-type Ca current (ICa,L), demonstrating PI3Kγ locally regulates cAMP levels in cardiomyocytes. Because phosphodiesterases (PDEs) can contribute to cAMP compartmentation, we examined whether the PDE activity was altered by PI3Kγ ablation. Selective inhibition of PDE3 or PDE4 in wild-type (WT) cardiomyocytes elevated Ca transients, SR Ca content, and phospholamban phosphorylation (PLN-PO4) by similar amounts to levels observed in untreated PI3Kγ myocytes. Combined PDE3 and PDE4 inhibition caused no further increases in SR function. By contrast, only PDE3 inhibition affected Ca transients, SR Ca loads, and PLN-PO4 levels in PI3Kγ myocytes. On the other hand, inhibition of PDE3 or PDE4 alone did not affect ICa,L in either PI3Kγ or WT cardiomyocytes, whereas simultaneous PDE3 and PDE4 inhibition elevated ICa,L in both groups. Ryanodine receptor (RyR2) phosphorylation levels were not different in basal conditions between PI3Kγ and WT myocytes and increased in both groups with PDE inhibition. Our results establish that L-type Ca channels, RyR2, and SR Ca pumps are regulated differently in distinct subcellular compartments by PDE3 and PDE4. In addition, the loss of PI3Kγ selectively abolishes PDE4 activity, not PDE3, in subcellular compartments containing the SR Ca-ATPase but not RyR2 or L-type Ca channels.