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Electrical and Ca2+-handling remodeling have been implicated in SAN dysfunction associated with heart failure, aging, and diabetes. Cardiomyocyte [Na+]i is also elevated in these diseases, where it contributes to arrhythmogenesis. Here, we sought to investigate the largely unexplored role of Na+ homeostasis in SAN pacemaking and test whether [Na+]i dysregulation may contribute to SAN dysfunction. Methods: We developed a dataset-specific computational model of the murine SAN myocyte and simulated alterations in the major processes of Na+ entry (Na+\/Ca2+ exchanger, NCX) and removal (Na+\/K+ ATPase, NKA). Results: We found that changes in intracellular Na+ 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 Ca2+ and membrane potential clocks underlying SAN firing. Conclusions: Our study generates new testable predictions and insight linking Na+ homeostasis to Ca2+ handling and membrane potential dynamics in SAN myocytes that may advance our understanding of SAN (dys)function.<\/jats:p>","DOI":"10.3390\/ijms22115645","type":"journal-article","created":{"date-parts":[[2021,5,26]],"date-time":"2021-05-26T10:30:32Z","timestamp":1622025032000},"page":"5645","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Intracellular Na+ Modulates Pacemaking Activity in Murine Sinoatrial Node Myocytes: An In Silico Analysis"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8679-665X","authenticated-orcid":false,"given":"Stefano","family":"Morotti","sequence":"first","affiliation":[{"name":"Department of Pharmacology, University of California Davis, Davis, CA 95616, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haibo","family":"Ni","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of California Davis, Davis, CA 95616, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8557-9100","authenticated-orcid":false,"given":"Colin H.","family":"Peters","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian","family":"Rickert","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ameneh","family":"Asgari-Targhi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of California Davis, Davis, CA 95616, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daisuke","family":"Sato","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of California Davis, Davis, CA 95616, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2076-9688","authenticated-orcid":false,"given":"Alexey V.","family":"Glukhov","sequence":"additional","affiliation":[{"name":"Department of Medicine, Cardiovascular Medicine, University of Wisconsin Madison School of Medicine and Public Health, Madison, WI 53705, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4324-6206","authenticated-orcid":false,"given":"Catherine","family":"Proenza","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"},{"name":"Department of Medicine, Division of Cardiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eleonora","family":"Grandi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of California Davis, Davis, CA 95616, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1392","DOI":"10.1111\/j.1540-8159.2010.02838.x","article-title":"The anatomy and physiology of the sinoatrial node-a contemporary review: Sinoatrial nodal anatomy and physiology","volume":"33","author":"Monfredi","year":"2010","journal-title":"Pacing Clin. 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