Published online before print April 28, 2005, doi: 10.1161/01.RES.0000168066.06333.df
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Submitted on October 28, 2004
Revised on March 17, 2005
Accepted on April 14, 2005
Cardiac Sarcoplasmic Reticulum Calcium Release and Load Are Enhanced by Subcellular cAMP Elevations in PI3K
-Deficient Mice
Benoit-Gilles Kerfant ;
From the Departments of Physiology and Medicine (B.-G.K., D.G., H.S., G.Y.O., P.H.B.), University of Toronto, Heart & Stroke Richard Lewar Centre, Toronto, Canada.; and the IMBA Institute of Molecular Biotechnology of the Austrian Academy of Sciences (J.M.P.), Vienna, Austria.
* To whom correspondence should be addressed. E-mail: p.backx{at}utoronto.ca.
We recently showed that phosphoinositide-3-kinase-
-deficient (PI3K-/-) mice have increased cardiac contractility without changes in heart size compared with control mice (ie, PI3K+/+ or PI3K+/-). In this study, we show that PI3K-/- cardiomyocytes have elevated Ca2+ transient amplitudes with abbreviated decay kinetics compared with control under field-stimulation and voltage-clamp conditions. When Ca2+ transients were eliminated with high Ca2+ buffering, L-type Ca2+ currents (ICa,L), K+ currents, and action potential duration (APD) were not different between the groups, whereas, in the presence of Ca2+ transients, Ca2+-dependent phase of ICa,L inactivation was abbreviated and APD at 90% repolarization was prolonged in PI3K-/- mice. Excitation-contraction coupling (ECC) gain, sarcoplasmic reticulum (SR) Ca2+ load, measured as caffeine-induced Na+/Ca2+ exchanger current integration and SR Ca2+ release fluxes measured as Ca2+ spikes, were also increased in PI3K-/- cardiomyocytes without detectable changes in Ca2+ spikes kinetics. The cAMP inhibitor Rp-cAMP eliminated enhanced ECC and SR Ca2+ load in PI3K-/- without effects in control myocytes. On the other hand, the 
-adrenergic receptor agonist isoproterenol increased ICa,L and Ca2+ transient equally by 
2-fold in both PI3K-/- and PI3K+/- cardiomyocytes. Our results establish that PI3K reduces cardiac contractility in a highly compartmentalized manner by inhibiting cAMP-mediated SR Ca2+ loading without directly affecting other major modulators of ECC, such as AP and ICa,L.
Key words: heart • PI3K
•
Ca2+ transient •
Ca2+ spikes •
cAMP
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