Effects of Sarcolemmal Background Ca2+ Entry and Sarcoplasmic Ca2+ Leak Currents on Electrophysiology and Ca2+ Transients in Human Ventricular Cardiomyocytes: A Computational Comparison.

The intricate regulation of the compartmental Ca²⁺ 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 Ca²⁺ dysregulation. Of interest to this investigation are two types of Ca²⁺ currents in cardiomyocytes: 1) background Ca²⁺ entry, i.e., Ca²⁺ transport across the sarcolemma from the extracellular space into the cytosol, and 2) Ca²⁺ leak from the sarcoplasmic reticulum (SR) across the SR membrane into the cytosol. Candidates for the ion channels underlying background Ca²⁺ entry and SR Ca²⁺ 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 Ca²⁺ entry and SR Ca²⁺ leak to the modulation of Ca²⁺ transients and SR Ca²⁺ load at rest and during action potentials. Background Ca²⁺ entry exhibited a positive relationship with both [Ca²⁺]_i and [Ca²⁺]_SR. Modulating SR Ca²⁺ leak had opposite effects of background Ca²⁺ entry. Effects of SR Ca²⁺ leak on Ca²⁺ were particularly pronounced at lower pacing frequency. In contrast to the pronounced effects of background and leak Ca²⁺ currents on Ca²⁺ concentrations, the effects on cellular electrophysiology were marginal. Our studies provide quantitative insights into the differential modulation of compartmental Ca²⁺ concentrations by the background and leak Ca²⁺ 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 Ca²⁺ currents and their contribution to the development of disease caused by Ca²⁺ dysregulation. [ABSTRACT FROM AUTHOR]