Effects of Sarcolemmal Background Ca Entry and Sarcoplasmic Ca Leak Currents on Electrophysiology and Ca Transients in Human Ventricular Cardiomyocytes: A Computational Comparison.

The intricate regulation of the compartmental Ca concentrations in cardiomyocytes is critical for electrophysiology, excitation-contraction coupling, and other signaling pathways. Research into the complex signaling pathways is motivated by cardiac pathologies including arrhythmia and maladaptive myocyte remodeling, which result from Ca dysregulation. Of interest to this investigation are two types of Ca currents in cardiomyocytes: 1) background Ca entry, i.e., Ca transport across the sarcolemma from the extracellular space into the cytosol, and 2) Ca leak from the sarcoplasmic reticulum (SR) across the SR membrane into the cytosol. Candidates for the ion channels underlying background Ca entry and SR Ca leak channels include members of the mechano-modulated transient receptor potential (TRP) family. We used a mathematical model of a human ventricular myocyte to analyze the individual contributions of background Ca entry and SR Ca leak to the modulation of Ca transients and SR Ca load at rest and during action potentials. Background Ca entry exhibited a positive relationship with both [Ca] and [Ca]. Modulating SR Ca leak had opposite effects of background Ca entry. Effects of SR Ca leak on Ca were particularly pronounced at lower pacing frequency. In contrast to the pronounced effects of background and leak Ca currents on Ca concentrations, the effects on cellular electrophysiology were marginal. Our studies provide quantitative insights into the differential modulation of compartmental Ca concentrations by the background and leak Ca currents. Furthermore, our studies support the hypothesis that TRP channels play a role in strain-modulation of cardiac contractility. In summary, our investigations shed light on the physiological effects of the background and leak Ca currents and their contribution to the development of disease caused by Ca dysregulation.