Referenced in: none

Automatically associated channels: Kv1.4 , Kv3.1 , Kv4.3

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

Authors: Thitima Keskanokwong, Hyun Joung Lim, Peng Zhang, Jun Cheng, Lin Xu, Dongwu Lai, Yanggan Wang

Journal, date & volume: Eur. Heart J., 2011 Feb , 32, 305-15

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/21148163

Abstract
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.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.Our results uncovered an important mechanism that regulates CaMKII activation in the heart and implicate I(to) channel alteration in pathological CaMKII activation.