Effects of Sarcolemmal Background Ca(2+) Entry and Sarcoplasmic Ca(2+) Leak Currents on Electrophysiology and Ca(2+) Transients in Human Ventricular Cardiomyocytes: A Computational Comparison

The intricate regulation of the compartmental Ca(2+) 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(2+) dysregulation. Of interest to this investigation are two types of Ca(2+) currents in cardiomyocytes: 1) background Ca(2+) entry, i.e., Ca(2+) transport across the sarcolemma from the extracellular space into the cytosol, and 2) Ca(2+) leak from the sarcoplasmic reticulum (SR) across the SR membrane into the cytosol. Candidates for the ion channels underlying background Ca(2+) entry and SR Ca(2+) 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(2+) entry and SR Ca(2+) leak to the modulation of Ca(2+) transients and SR Ca(2+) load at rest and during action potentials. Background Ca(2+) entry exhibited a positive relationship with both [Ca(2+)](i) and [Ca(2+)](SR). Modulating SR Ca(2+) leak had opposite effects of background Ca(2+) entry. Effects of SR Ca(2+) leak on Ca(2+) were particularly pronounced at lower pacing frequency. In contrast to the pronounced effects of background and leak Ca(2+) currents on Ca(2+) concentrations, the effects on cellular electrophysiology were marginal. Our studies provide quantitative insights into the differential modulation of compartmental Ca(2+) concentrations by the background and leak Ca(2+) 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(2+) currents and their contribution to the development of disease caused by Ca(2+) dysregulation.