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Using phosphoproteomic analysis of NaV channel complexes from adult mouse left ventricles, we identified nine phosphorylation sites on intracellular fibroblast growth factor 13 (iFGF13). To explore the potential roles of these phosphosites in regulating cardiac NaV currents, we abolished expression of iFGF13 in neonatal and adult mouse ventricular myocytes and rescued it with wild-type (WT), phosphosilent, or phosphomimetic iFGF13-VY. While the increased rate of closed-state inactivation of NaV channels induced by Fgf13 knockout in adult cardiomyocytes was completely restored by adenoviral-mediated expression of WT iFGF13-VY, only partial rescue was observed in neonatal cardiomyocytes after knockdown. The knockdown of iFGF13 in neonatal ventricular myocytes also shifted the voltage dependence of channel activation toward hyperpolarized potentials, a shift that was not reversed by WT iFGF13-VY expression. Additionally, we found that iFGF13-VY is the predominant isoform in adult ventricular myocytes, whereas both iFGF13-VY and iFGF13-S are expressed comparably in neonatal ventricular myocytes. Similar to WT iFGF13-VY, each of the iFGF13-VY phosphomutants studied restored NaV channel inactivation properties in both models. Lastly, Fgf13 knockout also increased the late Na+ current in adult cardiomyocytes, and this effect was restored with expression of WT and phosphosilent iFGF13-VY. Together, our results demonstrate that iFGF13 is highly phosphorylated and displays differential isoform expression in neonatal and adult ventricular myocytes. While we found no roles for iFGF13 phosphorylation, our results demonstrate differential effects of iFGF13 on neonatal and adult mouse ventricular NaV channels.<\/jats:p>","DOI":"10.1085\/jgp.202213293","type":"journal-article","created":{"date-parts":[[2023,7,1]],"date-time":"2023-07-01T02:20:46Z","timestamp":1688178046000},"update-policy":"https:\/\/doi.org\/10.1085\/jgp.crossmarkpolicy","source":"Crossref","is-referenced-by-count":13,"title":["Determinants of iFGF13-mediated regulation of myocardial voltage-gated sodium (NaV) channels in mouse"],"prefix":"10.1085","volume":"155","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8188-9168","authenticated-orcid":true,"given":"Adrien","family":"Lesage","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/049kkt456","id-type":"ROR","asserted-by":"publisher"}],"name":"CNRS, INSERM, L\u2019institut du Thorax 1 , , Nantes, France"},{"name":"Nantes Universit\u00e9 1 , , Nantes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5431-8274","authenticated-orcid":true,"given":"Maxime","family":"Lorenzini","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/049kkt456","id-type":"ROR","asserted-by":"publisher"}],"name":"CNRS, INSERM, L\u2019institut du Thorax 1 , , Nantes, France"},{"name":"Nantes Universit\u00e9 1 , , Nantes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0557-3396","authenticated-orcid":true,"given":"Sophie","family":"Burel","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/049kkt456","id-type":"ROR","asserted-by":"publisher"}],"name":"CNRS, INSERM, L\u2019institut du Thorax 1 , , Nantes, France"},{"name":"Nantes Universit\u00e9 1 , , Nantes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-9887-0014","authenticated-orcid":true,"given":"Marine","family":"Sarlandie","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/049kkt456","id-type":"ROR","asserted-by":"publisher"}],"name":"CNRS, INSERM, L\u2019institut du Thorax 1 , , Nantes, France"},{"name":"Nantes Universit\u00e9 1 , , Nantes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-8212-0908","authenticated-orcid":true,"given":"Floriane","family":"Bibault","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/049kkt456","id-type":"ROR","asserted-by":"publisher"}],"name":"CNRS, INSERM, L\u2019institut du Thorax 1 , , Nantes, France"},{"name":"Nantes Universit\u00e9 1 , , Nantes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5611-1015","authenticated-orcid":true,"given":"Cecilia","family":"Lindskog","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/048a87296","id-type":"ROR","asserted-by":"publisher"}],"name":"Cancer Precision Medicine, Uppsala University 2 Department of Immunology, Genetics and Pathology, , Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3239-2937","authenticated-orcid":true,"given":"Daniel","family":"Maloney","sequence":"additional","affiliation":[{"name":"Bioinformatics Solutions Inc. 3 , Waterloo, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3696-3955","authenticated-orcid":true,"given":"Jonathan R.","family":"Silva","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01yc7t268","id-type":"ROR","asserted-by":"publisher"}],"name":"Washington University in St. Louis 4 Department of Biomedical Engineering, , St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0753-7594","authenticated-orcid":true,"given":"R. 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