Dynamic Kv4.3-CaMKII unit in heart: an intrinsic negative regulator for CaMKII activation

Aims Reduction of transient outward current (I-to) and excessive activation of Ca2+/Calmodulin-dependent kinase II (CaMKII) are general features of ventricular myocytes in heart failure. We hypothesize that alterations of I-to directly regulate CaMKII activation in cardiomyocytes. Methods and results A dynamic coupling of I-to channel subunit Kv4.3 and inactive CaMKII was discovered in cardiomyocytes with the membrane predominant distribution by co-immunoprecipitation and fluorescence resonance energy transfer techniques. CaMKII dissociation from Kv4.3 CaMKII units caused a significant increase in CaMKII autophosphorylation and L-type calcium current (I-Ca) facilitation. I-Ca facilitation was blunted by the compartmental Ca2+ chelator BAPTA but unaffected by bulk Ca2+ chelator EGTA, implicating membrane-localized CaMKII. Kv4.3 overexpression reduced basal CaMKII autophosphorylation in myocytes and eliminated Ca2+-induced CaMKII activation. Kv4.3 blocks CaMKII activation by binding to the calmodulin binding sites, whereas Kv4.3 uncoupling releases these sites and leads to a substantial CaMKII activation. Conclusion Our results uncovered an important mechanism that regulates CaMKII activation in the heart and implicate Ito channel alteration in pathological CaMKII activation.