Streiff Molly E, Sachse Frank B
Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT, United States.
Department of Biomedical Engineering, University of Utah, Salt Lake City, UT, United States.
Front Physiol. 2022 Jun 16;13:916278. doi: 10.3389/fphys.2022.916278. eCollection 2022.
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.
心肌细胞内区室钙浓度的复杂调节对于电生理学、兴奋-收缩偶联及其他信号通路至关重要。对复杂信号通路的研究源于包括心律失常和适应性不良的心肌细胞重塑在内的心脏疾病，这些疾病是由钙调节异常导致的。本研究感兴趣的是心肌细胞中的两种钙电流：1）背景钙内流，即钙从细胞外空间穿过肌膜进入胞质溶胶的转运；2）钙从肌浆网（SR）穿过SR膜泄漏到胞质溶胶中。背景钙内流和SR钙泄漏通道潜在的离子通道候选者包括机械调制型瞬时受体电位（TRP）家族成员。我们使用人类心室肌细胞的数学模型来分析背景钙内流和SR钙泄漏在静息和动作电位期间对钙瞬变和SR钙负荷调节的各自贡献。背景钙内流与[Ca]和[Ca]均呈正相关。调节SR钙泄漏对背景钙内流有相反的影响。SR钙泄漏对钙的影响在较低起搏频率时尤为明显。与背景和泄漏钙电流对钙浓度的显著影响相反，它们对细胞电生理学的影响很小。我们的研究提供了关于背景和泄漏钙电流对区室钙浓度差异调节的定量见解。此外，我们的研究支持TRP通道在心脏收缩力应变调节中起作用的假说。总之，我们的研究揭示了背景和泄漏钙电流的生理效应及其对钙调节异常所致疾病发展的贡献。
