Late Na(+) current (I(NaL)) and Ca(2+)/calmodulin-dependent protein kinase II 
(CaMKII) are both increased in the diseased heart. Recently, CaMKII was found to 
phosphorylate the Na(+) channel 1.5 (Na(v)1.5), resulting in enhanced I(NaL). 
Conversely, an increase of I(NaL) would be expected to cause elevation of 
intracellular Ca(2+) and activation of CaMKII. However, a relationship between 
enhancement of I(NaL) and activation of CaMKII has yet to be demonstrated. We 
investigated whether Na(+) influx via Na(v)1.5 leads to CaMKII activation and 
explored the functional significance of this pathway. In neonatal rat 
ventricular myocytes (NRVM), treatment with the I(NaL) 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(v)1.5 (but not Na(v)1.1 or Na(v)1.2) prevented ATX-II-induced 
CaMKII phosphorylation, providing evidence for a specific role of Na(v)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(v)1.5 mutant 
(N(1325)S). The effects of both ATX-II and the N(1325)S mutation were reversed 
by either I(NaL) inhibition (with ranolazine or tetrodotoxin) or CaMKII 
inhibition (with KN93 or autocamtide 2-related inhibitory peptide). Furthermore, 
ATX-II treatment also induced CaMKII-Na(v)1.5 coimmunoprecipitation. The same 
association between CaMKII and Na(v)1.5 was also found in N(1325)S mice, 
suggesting a direct protein-protein interaction. Pharmacological inhibitions of 
either CaMKII or I(NaL) 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(v)1.5-dependent increase in Na(+) influx leads to activation of CaMKII, which 
in turn phosphorylates Na(v)1.5, further promoting Na(+) influx. Pharmacological 
inhibition of either CaMKII or Na(v)1.5 can ameliorate cardiac dysfunction 
caused by excessive Na(+) influx.