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Nedd4\u20102, which is activated by calcium, post\u2010translationally modulates Nav1.5. We aim to investigate whether elevated intracellular calcium ([Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>) reduces Nav1.5 through Nedd4\u20102 and its role in heart failure (<jats:styled-content style=\"fixed-case\">HF<\/jats:styled-content>).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Using a combination of biochemical, electrophysiological, cellular and<jats:italic>in\u00a0vivo<\/jats:italic>methods, we tested the effect and mechanism of calcium on Nedd4\u20102 and in turn Nav1.5.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Increased [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>, following 24\u2010h ionomycin treatment, decreased sodium current (<jats:styled-content style=\"fixed-case\"><jats:italic>I<\/jats:italic><jats:sub>N<\/jats:sub><\/jats:styled-content><jats:sub>a<\/jats:sub>) density and Nav1.5 protein without altering its<jats:styled-content style=\"fixed-case\">mRNA<\/jats:styled-content>in both neonatal rat cardiomyocytes (<jats:styled-content style=\"fixed-case\">NRCM<\/jats:styled-content>s) and<jats:styled-content style=\"fixed-case\">HEK<\/jats:styled-content>293 cells stably expressing Nav1.5. The calcium chelator<jats:styled-content style=\"fixed-case\">BAPTA<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">AM<\/jats:styled-content>restored the reduced Nav1.5 and<jats:styled-content style=\"fixed-case\"><jats:italic>I<\/jats:italic><jats:sub>N<\/jats:sub><\/jats:styled-content><jats:sub>a<\/jats:sub>in<jats:styled-content style=\"fixed-case\">NRCM<\/jats:styled-content>s pre\u2010treated by ionomycin. Nav1.5 was decreased by Nedd4\u20102 transfection and further decreased by 6\u2010h ionomycin treatment. These effects were not observed in cells transfected with the catalytically inactive mutant, Nedd4\u20102 C801S, or with Y1977A\u2010Nav1.5 mutant containing the impaired Nedd4\u20102 binding motif. Furthermore, elevated [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>increased Nedd4\u20102, the interaction between Nedd4\u20102 and Nav1.5, and Nav1.5 ubiquitination. Nav1.5 protein is decreased, whereas Nedd4\u20102 is increased in volume\u2010overload<jats:styled-content style=\"fixed-case\">HF<\/jats:styled-content>rat hearts, with increased co\u2010localization of Nav1.5 with ubiquitin or Nedd4\u20102 as indicated by immunofluorescence staining.<jats:styled-content style=\"fixed-case\">BAPTA<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">AM<\/jats:styled-content>rescued the reduced Nav1.5 protein,<jats:styled-content style=\"fixed-case\"><jats:italic>I<\/jats:italic><jats:sub>N<\/jats:sub><\/jats:styled-content><jats:sub>a<\/jats:sub>and increased Nedd4\u20102 in hypertrophied<jats:styled-content style=\"fixed-case\">NRCM<\/jats:styled-content>s induced by isoproterenol or angiotensin<jats:styled-content style=\"fixed-case\">II<\/jats:styled-content>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Calcium\u2010mediated increases in Nedd4\u20102 downregulate Nav1.5 by ubiquitination. Nav1.5 is downregulated and co\u2010localizes with Nedd4\u20102 and ubiquitin in failing rat heart. These data suggest a role of Nedd4\u20102 in Nav1.5 downregulation in<jats:styled-content style=\"fixed-case\">HF<\/jats:styled-content>.<\/jats:p><\/jats:sec>","DOI":"10.1111\/apha.12872","type":"journal-article","created":{"date-parts":[[2017,3,10]],"date-time":"2017-03-10T17:52:35Z","timestamp":1489168355000},"page":"44-58","source":"Crossref","is-referenced-by-count":49,"title":["Calcium\u2010dependent Nedd4\u20102 upregulation mediates degradation of the cardiac sodium channel Nav1.5: implications for heart failure"],"prefix":"10.1111","volume":"221","author":[{"given":"L.","family":"Luo","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Medicine First Affiliated Hospital of Xi'an Jiaotong University Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F.","family":"Ning","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine First Affiliated Hospital of Xi'an Jiaotong University Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y.","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine First Affiliated Hospital of Xi'an Jiaotong University Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B.","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine First Affiliated Hospital of Xi'an Jiaotong University Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D.","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine First Affiliated Hospital of Xi'an Jiaotong University Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. 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