Year: 2010
Type: article
Abstract: AIMS: Reduction of transient outward current (I(to)) and excessive activation of Ca(2+)/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 I(to) channel alteration in pathological CaMKII activation.
Source: European Heart Journal
Institutions: Emory University, Children's Healthcare of Atlanta
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2000587413