PMID:21677263

Citation	Yao, L, Fan, P, Jiang, Z, Viatchenko-Karpinski, S, Wu, Y, Kornyeyev, D, Hirakawa, R, Budas, GR, Rajamani, S, Shryock, JC and Belardinelli, L (2011) Nav1.5-dependent persistent Na+ influx activates CaMKII in rat ventricular myocytes and N1325S mice. Am. J. Physiol., Cell Physiol. 301:C577-86
Abstract	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.
Links	PubMed Online version:10.1152/ajpcell.00125.2011
Keywords	Acetanilides/pharmacology; Acetanilides/therapeutic use; Amino Acid Substitution/physiology; Animals; Animals, Newborn; Calcium/metabolism; Calcium Signaling/drug effects; Calcium Signaling/physiology; Calcium-Binding Proteins/metabolism; Calcium-Calmodulin-Dependent Protein Kinase Type 2/antagonists & inhibitors; Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism; Caspase 3/metabolism; Cell Death/drug effects; Cell Survival/drug effects; Cnidarian Venoms/pharmacology; Dose-Response Relationship, Drug; Electrophysiological Phenomena/drug effects; Electrophysiological Phenomena/physiology; Female; Gene Expression/drug effects; Heart Ventricles/cytology; Heart Ventricles/drug effects; Heart Ventricles/metabolism; Humans; Mice; Mice, Inbred Strains; Mice, Transgenic; Myocytes, Cardiac/drug effects; Myocytes, Cardiac/metabolism; NAV1.5 Voltage-Gated Sodium Channel; Peptides/pharmacology; Peptides/therapeutic use; Perfusion; Phosphorylation/drug effects; Piperazines/pharmacology; Piperazines/therapeutic use; Protein Binding/drug effects; Protein Binding/physiology; RNA, Small Interfering/genetics; Rabbits; Rats; Rats, Sprague-Dawley; Ryanodine Receptor Calcium Release Channel/metabolism; Sodium/metabolism; Sodium Channels/genetics; Sodium Channels/metabolism; Sodium-Calcium Exchanger/antagonists & inhibitors; Sodium-Calcium Exchanger/metabolism; Tachycardia, Ventricular/chemically induced; Tachycardia, Ventricular/prevention & control; Tetrodotoxin/pharmacology; Veratridine/pharmacology
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
RAT:KCC2D		GO:0005954: calcium- and calmodulin-dependent protein kinase complex	ECO:0000314:		C		Figure 3: Immunoblot shows CaMKIId forms complex and increases activity of sodium channel	complete CACAO 8167

References

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