Cardiac Sarcoplasmic Reticulum Calcium Release and Load Are Enhanced by Subcellular cAMP Elevations in PI3Kγ-Deficient Mice

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Abstract
We recently showed that phosphoinositide-3-kinase-γ–deficient (PI3Kγ−/−) mice have increased cardiac contractility without changes in heart size compared with control mice (ie, PI3Kγ+/+ or PI3Kγ+/−). In this study, we show that PI3Kγ−/− 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 PI3Kγ−/− mice. Excitation-contraction coupling (ECC) gain, sarcoplasmic reticulum (SR) Ca2+ load, and SR Ca2+ release fluxes measured as Ca2+ spikes, were also increased in PI3Kγ−/− cardiomyocytes without detectable changes in Ca2+ spikes kinetics. The cAMP inhibitor Rp-cAMP eliminated enhanced ECC and SR Ca2+ load in PI3Kγ−/− without effects in control myocytes. On the other hand, the β-adrenergic receptor agonist isoproterenol increased ICa,L and Ca2+ transient equally by ≈2-fold in both PI3Kγ−/− and PI3Kγ+/− cardiomyocytes. Our results establish that PI3Kγ 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.

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