Role of SERCA and the sarcoplasmic reticulum calcium content on calcium waves propagation in rat ventricular myocytes
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© 2016 Elsevier Inc.In Ca2+-overloaded ventricular myocytes, SERCA is crucial to steadily achieve the critical sarcoplasmic reticulum (SR) Ca2+ level to trigger and sustain Ca2+ waves, that propagate at constant rate (¿wave). High luminal Ca2+ sensitizes RyR2, thereby increasing Ca2+ sparks frequency, and the larger RyR2-mediated SR Ca2+ flux (dF/dt) sequentially activates adjacent RyR2 clusters. Recently, it was proposed that rapid SERCA Ca2+ reuptake, ahead of the wave front, further sensitizes RyR2, increasing ¿wave. Nevertheless, this is controversial because rapid cytosolic Ca2+ removal could instead impair RyR2 activation. We assessed whether rapid SR Ca2+ uptake enhances ¿wave by changing SERCA activity (¿Decay) over a large range (~175%). We used normal (Ctrl) and hyperthyroid rat (HT; reduced phospholamban by ~80%) myocytes treated with thapsigargin or isoproterenol (ISO). We found that ¿wave and dF/dt had a non-linear dependency with ¿Decay, while Ca2+ waves amplitude was largely unaffected. Furthermore, SR Ca2+ also showed a non-linear dependency with ¿Decay, however, the relationships ¿wave vs. SR Ca2+ and ¿wave vs. dF/dt were linear, suggesting that high steady state SR Ca2+ determines ¿wave, while rapid SERCA Ca2+ uptake does not. Finally, ISO did not increase ¿wave in HT cells, therefore, ISO-enhanced ¿wave in Ctrl depended on high SR Ca2+.