In:
American Journal of Physiology-Cell Physiology, American Physiological Society, Vol. 301, No. 3 ( 2011-09), p. C577-C586
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.
Type of Medium:
Online Resource
ISSN:
0363-6143
,
1522-1563
DOI:
10.1152/ajpcell.00125.2011
Language:
English
Publisher:
American Physiological Society
Publication Date:
2011
detail.hit.zdb_id:
1477334-X
SSG:
12
