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...
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| Format: | Article |
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Frontiers Media S.A.
2022-06-01
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| Series: | Frontiers in Physiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphys.2022.916278/full |
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| author | Molly E. Streiff Molly E. Streiff Frank B. Sachse Frank B. Sachse |
| author_facet | Molly E. Streiff Molly E. Streiff Frank B. Sachse Frank B. Sachse |
| author_sort | Molly E. Streiff |
| collection | DOAJ |
| description | 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. |
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| id | doaj.art-b70548eacb2546f1aaf2ad33e0c0e640 |
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| issn | 1664-042X |
| language | English |
| last_indexed | 2024-12-12T09:21:41Z |
| publishDate | 2022-06-01 |
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| series | Frontiers in Physiology |
| spelling | doaj.art-b70548eacb2546f1aaf2ad33e0c0e6402022-12-22T00:29:12ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2022-06-011310.3389/fphys.2022.916278916278Effects of Sarcolemmal Background Ca2+ Entry and Sarcoplasmic Ca2+ Leak Currents on Electrophysiology and Ca2+ Transients in Human Ventricular Cardiomyocytes: A Computational ComparisonMolly E. Streiff0Molly E. Streiff1Frank B. Sachse2Frank B. Sachse3Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT, United StatesDepartment of Biomedical Engineering, University of Utah, Salt Lake City, UT, United StatesNora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT, United StatesDepartment of Biomedical Engineering, University of Utah, Salt Lake City, UT, United StatesThe 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.https://www.frontiersin.org/articles/10.3389/fphys.2022.916278/fullcalciumcardiomyocytesarcolemmasarcoplasmic reticulumleak |
| spellingShingle | Molly E. Streiff Molly E. Streiff Frank B. Sachse Frank B. Sachse Effects of Sarcolemmal Background Ca2+ Entry and Sarcoplasmic Ca2+ Leak Currents on Electrophysiology and Ca2+ Transients in Human Ventricular Cardiomyocytes: A Computational Comparison Frontiers in Physiology calcium cardiomyocyte sarcolemma sarcoplasmic reticulum leak |
| title | Effects of Sarcolemmal Background Ca2+ Entry and Sarcoplasmic Ca2+ Leak Currents on Electrophysiology and Ca2+ Transients in Human Ventricular Cardiomyocytes: A Computational Comparison |
| title_full | Effects of Sarcolemmal Background Ca2+ Entry and Sarcoplasmic Ca2+ Leak Currents on Electrophysiology and Ca2+ Transients in Human Ventricular Cardiomyocytes: A Computational Comparison |
| title_fullStr | Effects of Sarcolemmal Background Ca2+ Entry and Sarcoplasmic Ca2+ Leak Currents on Electrophysiology and Ca2+ Transients in Human Ventricular Cardiomyocytes: A Computational Comparison |
| title_full_unstemmed | Effects of Sarcolemmal Background Ca2+ Entry and Sarcoplasmic Ca2+ Leak Currents on Electrophysiology and Ca2+ Transients in Human Ventricular Cardiomyocytes: A Computational Comparison |
| title_short | Effects of Sarcolemmal Background Ca2+ Entry and Sarcoplasmic Ca2+ Leak Currents on Electrophysiology and Ca2+ Transients in Human Ventricular Cardiomyocytes: A Computational Comparison |
| title_sort | effects of sarcolemmal background ca2 entry and sarcoplasmic ca2 leak currents on electrophysiology and ca2 transients in human ventricular cardiomyocytes a computational comparison |
| topic | calcium cardiomyocyte sarcolemma sarcoplasmic reticulum leak |
| url | https://www.frontiersin.org/articles/10.3389/fphys.2022.916278/full |
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