Modeling sarcoplasmic reticulum Ca2+ in rat cardiomyocytes.

Abstract

The sarcoplasmic reticulum (SR) primarily serves as the intracellular Ca²⁺ store in cardiac myocytes, mediating cellular function under cardiac physiology and diseases. However, the properties of cardiac SR Ca²⁺ have not yet been fully determined, particularly in rats and mice, which are the most commonly used experimental species in studies on cardiac physiology and diseases. Here, we developed a spatially detailed numerical model to deduce Ca²⁺ movements inside the junctional SR (jSR) cisternae of rat cardiomyocytes. Our model accurately reproduced the jSR Ca²⁺ kinetics of local and global SR Ca²⁺ releases reported in a recent experimental study. With this model, we revealed that jSR Ca²⁺ kinetics was mostly determined by the total release flux via type 2 ryanodine receptor (RyR2) channels but not by RyR2 positioning. Although Ca²⁺ diffusion in global SR was previously reported to be slow, our simulation demonstrated that Ca²⁺ diffused very quickly inside local jSR cisternae and the decrease in the diffusion coefficient resulted in a significant reduction of jSR Ca²⁺ depletion amplitude. Intracellular Ca²⁺ was typically experimentally detected with fluorescence dye. Our simulation revealed that when the dynamical characteristics of fluorescence dye exerted a minimal effect on actual Ca²⁺ mobility inside jSR, the reaction rate of the dye with Ca²⁺ could significantly affect apparent jSR Ca²⁺ kinetics. Therefore, loading a chemical fluorescence dye with fast kinetics, such as Fluo-5N, into SR is important for Ca²⁺ measurement inside SR. Overall, our model provides new insights into deciphering Ca²⁺ handling inside nanoscopic jSR cisternae in rat cardiomyocytes.