Published online before print July 5, 2007, doi: 10.1161/CIRCRESAHA.107.156422
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Submitted on August 9, 2006
Revised on June 19, 2007
Accepted on June 26, 2007
PI3K
Is Required for PDE4, not PDE3, Activity in Subcellular Microdomians Containing the Sarcoplasmic Reticular Calcium ATPase in Cardiomyocytes
Benoit-Gilles Kerfant ;
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.
* To whom correspondence should be addressed. 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 (ICa,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 ICa,L in either PI3K-/- 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 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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