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(Circulation Research. 2007;101:400.)
© 2007 American Heart Association, Inc.

Cellular Biology

PI3K Is Required for PDE4, not PDE3, Activity in Subcellular Microdomains Containing the Sarcoplasmic Reticular Calcium ATPase in Cardiomyocytes

Benoit-Gilles Kerfant, Dongling Zhao, Ilka Lorenzen-Schmidt, Lindsay S. Wilson, Shitian Cai, S. R. Wayne Chen, Donald H. Maurice, Peter H. Backx

From the Departments of Physiology and Medicine, the Heart & Stroke Richard Lewar Centre, and the Division of Cardiology at the University Health Network (B.-G.K., D.Z., I.L.-S., P.H.B.), University of Toronto; the Departments of Pharmacology & Toxicology (L.S.W., D.H.M.), Queen’s University, Kingston; and the Departments of Physiology and Biophysics (S.C., S.R.W.C.), University of Calgary, Canada.

Correspondence to Peter H. Backx, DVM, PhD, Professor, 150 College St, Toronto, ON, M5S 3E2, Canada. E-mail p.backx{at}utoronto.ca

We recently showed that phosphoinositide-3-kinase-–deficient (PI3K^–/–) 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 PI3K locally regulates cAMP levels in cardiomyocytes. Because phosphodiesterases (PDEs) can contribute to cAMP compartmentation, we examined whether the PDE activity was altered by PI3K 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 PI3K^–/– 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 PI3K^–/– myocytes. On the other hand, inhibition of PDE3 or PDE4 alone did not affect I_Ca,L in either PI3K^–/– or WT cardiomyocytes, whereas simultaneous PDE3 and PDE4 inhibition elevated I_Ca,L in both groups. Ryanodine receptor (RyR₂) phosphorylation levels were not different in basal conditions between PI3K^–/– 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 PI3K selectively abolishes PDE4 activity, not PDE3, in subcellular compartments containing the SR Ca²⁺-ATPase but not RyR₂ or L-type Ca²⁺ channels.

Key Words: cardiomyocytes • PI3K • PDE3 • PDE4 • excitation-contraction-coupling

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