Role of SERCA and the sarcoplasmic reticulum calcium content on calcium waves propagation in rat ventricular myocytes

摘要

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 (upsilon(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 upsilon(wave). Nevertheless, this is controversial because rapid cytosolic Ca2+ removal could instead impair RyR2 activation. We assessed whether rapid SR Ca2+ uptake enhances upsilon(wave) by changing SERCA activity (kappa(Decay)) over a large range (similar to 175%). We used normal (Ctrl) and hyperthyroid rat (HT; reduced phospholamban by similar to 80%) myocytes treated with thapsigargin or isoproterenol (ISO). We found that upsilon(wave) and dF/dt had a non-linear dependency with kappa(Decay), while Ca2+ waves amplitude was largely unaffected. Furthermore, SR Ca2+ also showed a non-linear dependency with kappa(Decay), however, the relationships upsilon(wave) vs. SR Ca2+ and upsilon(wave) vs. dF/dt were linear, suggesting that high steady state SR Ca2+ determines upsilon(wave), while rapid SERCA Ca2+ uptake does not. Finally, ISO did not increase upsilon(wave) in HT cells, therefore, ISO-enhanced upsilon(wave) in Ctrl depended on high SR Ca2+. (C) 2016 Elsevier Inc. All rights reserved.