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

Abstract

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.

TRPC1 channels underlie stretch-modulated sarcoplasmic reticulum calcium leak in cardiomyocytes

“…SR Ca 2+ leak did not significantly affect resting membrane potential and exhibited only a marginal positive correlation with action potential duration. In another in situ study of a human ventricular myocyte, modulating SR Ca 2+ leak had negligible effects on both resting membrane potential and action potential duration at any pacing frequency (Streiff and Sachse, 2022). It seems unlikely that TRPC1 leak has a role in modulating myocyte electrophysiology in physiological conditions.…”

“…Another potential pathologic consequence of chronically increased SR leak through TRPC1 channels is increased susceptibility to arrhythmia. As has been discussed, primarily in the context of RyR leak, chronically increased SR leak makes cardiomyocytes increasingly susceptible to arrhythmias (Hannanta-Anan and Chow, 2016;Siri-Angkul et al, 2021;Streiff and Sachse, 2022). Indeed, recent studies suggested a link between TRPC-mediated currents and arrhythmogenesis (Wen et al, 2018;Siri-Angkul et al, 2021).…”

“…In our prior work, we explored the impact of TRPC1-mediated SR Ca 2+ leak on myocyte electrophysiology (Hu et al, 2020;Streiff and Sachse, 2022). In particular, we investigated the relationship between SR leak and the action potential using a computational model of rabbit ventricular myocytes (Hu et al, 2020).…”

Progress on role of ion channels of cardiac fibroblasts in fibrosis

“…Decreased calcium influx into cells reduces fibroblast differentiation, collagen release, and reduce TGF-β-induced fibrotic remodeling ( Ramires et al, 1998 ; Teng et al, 2015 ). Intracellular Ca 2+ signals are generated by Ca 2+ entry through Ca 2+ -permeable channels in the plasma membrane and by Ca 2+ release from intracellular Ca 2+ stores ( Feng et al, 2019 ; Maione et al, 2022 ; Streiff and Sachse, 2022 ). Intracellular Ca 2+ level is also precisely controlled by plasma membrane ATPase (PMCAs), Na + /Ca 2+ exchangers (NCX) and sarcoplasmic reticulum Ca 2+ -ATPase (SERCA) ( Kranias and Hajjar, 2012 ; Morotti et al, 2021 ).…”