Intracellular Na<sup>+</sup> Modulates Pacemaking Activity in Murine Sinoatrial Node Myocytes: An <i>In Silico</i> Analysis
<i>Background</i>: The mechanisms underlying dysfunction in the sinoatrial node (SAN), the heart’s primary pacemaker, are incompletely understood. Electrical and Ca<sup>2+</sup>-handling remodeling have been implicated in SAN dysfunction associated with heart failure, aging,...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-05-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/11/5645 |
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| author | Stefano Morotti Haibo Ni Colin H. Peters Christian Rickert Ameneh Asgari-Targhi Daisuke Sato Alexey V. Glukhov Catherine Proenza Eleonora Grandi |
| author_facet | Stefano Morotti Haibo Ni Colin H. Peters Christian Rickert Ameneh Asgari-Targhi Daisuke Sato Alexey V. Glukhov Catherine Proenza Eleonora Grandi |
| author_sort | Stefano Morotti |
| collection | DOAJ |
| description | <i>Background</i>: The mechanisms underlying dysfunction in the sinoatrial node (SAN), the heart’s primary pacemaker, are incompletely understood. Electrical and Ca<sup>2+</sup>-handling remodeling have been implicated in SAN dysfunction associated with heart failure, aging, and diabetes. Cardiomyocyte [Na<sup>+</sup>]<sub>i</sub> is also elevated in these diseases, where it contributes to arrhythmogenesis. Here, we sought to investigate the largely unexplored role of Na<sup>+</sup> homeostasis in SAN pacemaking and test whether [Na<sup>+</sup>]<sub>i</sub> dysregulation may contribute to SAN dysfunction. <i>Methods</i>: We developed a dataset-specific computational model of the murine SAN myocyte and simulated alterations in the major processes of Na<sup>+</sup> entry (Na<sup>+</sup>/Ca<sup>2+</sup> exchanger, NCX) and removal (Na<sup>+</sup>/K<sup>+</sup> ATPase, NKA). <i>Results</i>: We found that changes in intracellular Na<sup>+</sup> homeostatic processes dynamically regulate SAN electrophysiology. Mild reductions in NKA and NCX function increase myocyte firing rate, whereas a stronger reduction causes bursting activity and loss of automaticity. These pathologic phenotypes mimic those observed experimentally in NCX- and ankyrin-B-deficient mice due to altered feedback between the Ca<sup>2+</sup> and membrane potential clocks underlying SAN firing. <i>Conclusions</i>: Our study generates new testable predictions and insight linking Na<sup>+</sup> homeostasis to Ca<sup>2+</sup> handling and membrane potential dynamics in SAN myocytes that may advance our understanding of SAN (dys)function. |
| first_indexed | 2024-03-10T11:02:58Z |
| format | Article |
| id | doaj.art-f2077e3616a44d1e9eb72fefda775da6 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T11:02:58Z |
| publishDate | 2021-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-f2077e3616a44d1e9eb72fefda775da62023-11-21T21:25:12ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-05-012211564510.3390/ijms22115645Intracellular Na<sup>+</sup> Modulates Pacemaking Activity in Murine Sinoatrial Node Myocytes: An <i>In Silico</i> AnalysisStefano Morotti0Haibo Ni1Colin H. Peters2Christian Rickert3Ameneh Asgari-Targhi4Daisuke Sato5Alexey V. Glukhov6Catherine Proenza7Eleonora Grandi8Department of Pharmacology, University of California Davis, Davis, CA 95616, USADepartment of Pharmacology, University of California Davis, Davis, CA 95616, USADepartment of Physiology and Biophysics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USADepartment of Physiology and Biophysics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USADepartment of Pharmacology, University of California Davis, Davis, CA 95616, USADepartment of Pharmacology, University of California Davis, Davis, CA 95616, USADepartment of Medicine, Cardiovascular Medicine, University of Wisconsin Madison School of Medicine and Public Health, Madison, WI 53705, USADepartment of Physiology and Biophysics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USADepartment of Pharmacology, University of California Davis, Davis, CA 95616, USA<i>Background</i>: The mechanisms underlying dysfunction in the sinoatrial node (SAN), the heart’s primary pacemaker, are incompletely understood. Electrical and Ca<sup>2+</sup>-handling remodeling have been implicated in SAN dysfunction associated with heart failure, aging, and diabetes. Cardiomyocyte [Na<sup>+</sup>]<sub>i</sub> is also elevated in these diseases, where it contributes to arrhythmogenesis. Here, we sought to investigate the largely unexplored role of Na<sup>+</sup> homeostasis in SAN pacemaking and test whether [Na<sup>+</sup>]<sub>i</sub> dysregulation may contribute to SAN dysfunction. <i>Methods</i>: We developed a dataset-specific computational model of the murine SAN myocyte and simulated alterations in the major processes of Na<sup>+</sup> entry (Na<sup>+</sup>/Ca<sup>2+</sup> exchanger, NCX) and removal (Na<sup>+</sup>/K<sup>+</sup> ATPase, NKA). <i>Results</i>: We found that changes in intracellular Na<sup>+</sup> homeostatic processes dynamically regulate SAN electrophysiology. Mild reductions in NKA and NCX function increase myocyte firing rate, whereas a stronger reduction causes bursting activity and loss of automaticity. These pathologic phenotypes mimic those observed experimentally in NCX- and ankyrin-B-deficient mice due to altered feedback between the Ca<sup>2+</sup> and membrane potential clocks underlying SAN firing. <i>Conclusions</i>: Our study generates new testable predictions and insight linking Na<sup>+</sup> homeostasis to Ca<sup>2+</sup> handling and membrane potential dynamics in SAN myocytes that may advance our understanding of SAN (dys)function.https://www.mdpi.com/1422-0067/22/11/5645sodium homeostasissodium/potassium pumpsodium/calcium exchangersinoatrial nodecoupled-clock systemcardiomyocyte |
| spellingShingle | Stefano Morotti Haibo Ni Colin H. Peters Christian Rickert Ameneh Asgari-Targhi Daisuke Sato Alexey V. Glukhov Catherine Proenza Eleonora Grandi Intracellular Na<sup>+</sup> Modulates Pacemaking Activity in Murine Sinoatrial Node Myocytes: An <i>In Silico</i> Analysis International Journal of Molecular Sciences sodium homeostasis sodium/potassium pump sodium/calcium exchanger sinoatrial node coupled-clock system cardiomyocyte |
| title | Intracellular Na<sup>+</sup> Modulates Pacemaking Activity in Murine Sinoatrial Node Myocytes: An <i>In Silico</i> Analysis |
| title_full | Intracellular Na<sup>+</sup> Modulates Pacemaking Activity in Murine Sinoatrial Node Myocytes: An <i>In Silico</i> Analysis |
| title_fullStr | Intracellular Na<sup>+</sup> Modulates Pacemaking Activity in Murine Sinoatrial Node Myocytes: An <i>In Silico</i> Analysis |
| title_full_unstemmed | Intracellular Na<sup>+</sup> Modulates Pacemaking Activity in Murine Sinoatrial Node Myocytes: An <i>In Silico</i> Analysis |
| title_short | Intracellular Na<sup>+</sup> Modulates Pacemaking Activity in Murine Sinoatrial Node Myocytes: An <i>In Silico</i> Analysis |
| title_sort | intracellular na sup sup modulates pacemaking activity in murine sinoatrial node myocytes an i in silico i analysis |
| topic | sodium homeostasis sodium/potassium pump sodium/calcium exchanger sinoatrial node coupled-clock system cardiomyocyte |
| url | https://www.mdpi.com/1422-0067/22/11/5645 |
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