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We recently showed that phosphoinositide-3-kinase-γ–deficient (PI3Kγ−/− ) mice have enhanced cardiac contractility attributable to cAMP-dependent increases in sarcoplasmic reticulum (SR) Ca2+ content and release but not L-type Ca2+ current (I Ca,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 Ca2+ transients, SR Ca2+ 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 Ca2+ transients, SR Ca2+ loads, and PLN-PO4 levels in PI3Kγ−/− myocytes. On the other hand, inhibition of PDE3 or PDE4 alone did not affectI Ca,L in either PI3Kγ−/− or WT cardiomyocytes, whereas simultaneous PDE3 and PDE4 inhibition elevatedI Ca,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 Ca2+ channels, RyR2 , and SR Ca2+ 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 Ca2+ -ATPase but not RyR2 or L-type Ca2+ channels.

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