title: Dynamic Kv4.3-CaMKII unit in heart: an intrinsic negative regulator for CaMKII activation.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  Our results uncovered an important mechanism that regulates CaMKII activation in the heart and implicate I(to) channel alteration in pathological CaMKII activation.
authors.affiliation: Department of Pediatrics and Children's Healthcare of Atlanta, Emory University, Atlanta, GA 30322, USA.
authors.forename: Thitima
authors.initials: T
authors.lastname: Keskanokwong
authors.forename: Hyun Joung
authors.initials: HJ
authors.lastname: Lim
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.forename: Jun
authors.initials: J
authors.lastname: Cheng
authors.forename: Lin
authors.initials: L
authors.lastname: Xu
authors.forename: Dongwu
authors.initials: D
authors.lastname: Lai
authors.forename: Yanggan
authors.initials: Y
authors.lastname: Wang
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000502:physiology*; D002614:Chelating Agents / Q000494:pharmacology; D004492:Edetic Acid / Q000494:pharmacology; D004533:Egtazic Acid / Q000494:pharmacology; D057809:HEK293 Cells; D006331:Heart Diseases / Q000209:etiology / Q000517:prevention & control; D006801:Humans; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D051672:Shal Potassium Channels / Q000378:metabolism / Q000502:physiology*
chemical_list: D002614:Chelating Agents; D026902:Potassium Channel Blockers; D051672:Shal Potassium Channels; D004533:Egtazic Acid; D004492:Edetic Acid; D015761:4-Aminopyridine; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002118:Calcium