{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T03:02:59Z","timestamp":1791169379455,"version":"4.1.0"},"reference-count":57,"publisher":"American Physiological Society","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Cell Physiology"],"published-print":{"date-parts":[[2011,9]]},"abstract":"<jats:p> Late Na<jats:sup>+<\/jats:sup> current ( I<jats:sub>NaL<\/jats:sub>) and Ca<jats:sup>2+<\/jats:sup>\/calmodulin-dependent protein kinase II (CaMKII) are both increased in the diseased heart. Recently, CaMKII was found to phosphorylate the Na<jats:sup>+<\/jats:sup> channel 1.5 (Na<jats:sub>v<\/jats:sub>1.5), resulting in enhanced I<jats:sub>NaL<\/jats:sub>. Conversely, an increase of I<jats:sub>NaL<\/jats:sub> would be expected to cause elevation of intracellular Ca<jats:sup>2+<\/jats:sup> and activation of CaMKII. However, a relationship between enhancement of I<jats:sub>NaL<\/jats:sub> and activation of CaMKII has yet to be demonstrated. We investigated whether Na<jats:sup>+<\/jats:sup> influx via Na<jats:sub>v<\/jats:sub>1.5 leads to CaMKII activation and explored the functional significance of this pathway. In neonatal rat ventricular myocytes (NRVM), treatment with the I<jats:sub>NaL<\/jats:sub> activators anemone toxin II (ATX-II) or veratridine increased CaMKII autophosphorylation and increased phosphorylation of CaMKII substrates phospholamban and ryanodine receptor 2. Knockdown of Na<jats:sub>v<\/jats:sub>1.5 (but not Na<jats:sub>v<\/jats:sub>1.1 or Na<jats:sub>v<\/jats:sub>1.2) prevented ATX-II-induced CaMKII phosphorylation, providing evidence for a specific role of Na<jats:sub>v<\/jats:sub>1.5 in CaMKII activation. In support of this view, CaMKII activity was also increased in hearts of transgenic mice overexpressing a gain-of-function Na<jats:sub>v<\/jats:sub>1.5 mutant (N<jats:sub>1325<\/jats:sub>S). The effects of both ATX-II and the N<jats:sub>1325<\/jats:sub>S mutation were reversed by either I<jats:sub>NaL<\/jats:sub> inhibition (with ranolazine or tetrodotoxin) or CaMKII inhibition (with KN93 or autocamtide 2-related inhibitory peptide). Furthermore, ATX-II treatment also induced CaMKII-Na<jats:sub>v<\/jats:sub>1.5 coimmunoprecipitation. The same association between CaMKII and Na<jats:sub>v<\/jats:sub>1.5 was also found in N<jats:sub>1325<\/jats:sub>S mice, suggesting a direct protein-protein interaction. Pharmacological inhibitions of either CaMKII or I<jats:sub>NaL<\/jats:sub> also prevented ATX-II-induced cell death in NRVM and reduced the incidence of polymorphic ventricular tachycardia induced by ATX-II in rat perfused hearts. Taken together, these results suggest that a Na<jats:sub>v<\/jats:sub>1.5-dependent increase in Na<jats:sup>+<\/jats:sup> influx leads to activation of CaMKII, which in turn phosphorylates Na<jats:sub>v<\/jats:sub>1.5, further promoting Na<jats:sup>+<\/jats:sup> influx. Pharmacological inhibition of either CaMKII or Na<jats:sub>v<\/jats:sub>1.5 can ameliorate cardiac dysfunction caused by excessive Na<jats:sup>+<\/jats:sup> influx. <\/jats:p>","DOI":"10.1152\/ajpcell.00125.2011","type":"journal-article","created":{"date-parts":[[2011,6,16]],"date-time":"2011-06-16T04:27:42Z","timestamp":1308198462000},"page":"C577-C586","source":"Crossref","is-referenced-by-count":93,"title":["Na<sub>v<\/sub>1.5-dependent persistent Na<sup>+<\/sup> influx activates CaMKII in rat ventricular myocytes and N<sub>1325<\/sub>S mice"],"prefix":"10.1152","volume":"301","author":[{"given":"Lina","family":"Yao","sequence":"first","affiliation":[{"name":"Department of Biology, Gilead Sciences, Palo Alto, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peidong","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Biology, Gilead Sciences, Palo Alto, 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