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(Circulation Research. 2005;96:1079.)
© 2005 American Heart Association, Inc.

Cellular Biology

Cardiac Sarcoplasmic Reticulum Calcium Release and Load Are Enhanced by Subcellular cAMP Elevations in PI3K-Deficient Mice

Benoit-Gilles Kerfant^*, Dominica Gidrewicz^*, Hui Sun, Gavin Y. Oudit, Josef M. Penninger, Peter H. Backx

From the Departments of Physiology and Medicine. Heart & Stroke Richard Lewar Centre, and Division of Cardiology, University Health Network, University of Toronto (B.-G.K., D.G., H.S., G.Y.O., P.M.B.) Toronto, Canada.; and the IMBA Institute of Molecular Biotechnology of the Austrian Academy of Sciences (J.M.P.), Vienna, Austria.

Correspondence to Prof Peter H. Backx, DVM, PhD, Fitzgerald Building, Heart and Stroke/Richard Lewar Center, 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 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 (I_Ca,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 I_Ca,L inactivation was abbreviated and APD at 90% repolarization was prolonged in PI3K^–/– mice. Excitation-contraction coupling (ECC) gain, sarcoplasmic reticulum (SR) Ca²⁺ load, 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 ß-adrenergic receptor agonist isoproterenol increased I_Ca,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 I_Ca,L.

Key Words: heart • PI3K • Ca²⁺ transient • Ca²⁺ spikes • cAMP

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