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Isolation and Kv Channel Recordings in Murine Atrial and Ventricular Cardiomyocytes
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Dynamic Kv4.3-CaMKII unit in heart: an intrinsic negative regulator for CaMKII activation

Thitima Keskanokwong1, Hyun Joung Lim, Peng Zhang

  • 1Department of Pediatrics and Children's Healthcare of Atlanta, Emory University, Atlanta, GA 30322, USA.

European Heart Journal
|December 15, 2010
PubMed

Insights

Transient outward current (I(to)) alterations regulate Ca(2+)/Calmodulin-dependent kinase II (CaMKII) activation in heart failure. Kv4.3 channel interaction with CaMKII controls its activity, impacting cardiac function.

Area of Science:

  • Cardiovascular Physiology
  • Molecular Cardiology
  • Cardiac Electrophysiology

Background:

  • Heart failure is characterized by reduced transient outward current (I(to)) and overactive Ca(2+)/Calmodulin-dependent kinase II (CaMKII) in ventricular myocytes.
  • The precise relationship between I(to) and CaMKII activation in pathological conditions remains unclear.

Purpose of the Study:

  • To investigate the hypothesis that alterations in I(to) directly modulate CaMKII activation within cardiomyocytes.
  • To elucidate the molecular mechanisms linking I(to) channels to CaMKII signaling in the context of heart failure.

Main Methods:

  • Utilized co-immunoprecipitation and fluorescence resonance energy transfer (FRET) to detect dynamic coupling between I(to) channel subunit Kv4.3 and CaMKII.
  • Employed overexpression of Kv4.3 and utilized compartmental vs. bulk calcium chelators (BAPTA vs. EGTA) to assess CaMKII localization and activation.

Main Results:

  • Discovered a membrane-localized dynamic association between Kv4.3 and CaMKII.
  • CaMKII dissociation from Kv4.3 led to increased CaMKII autophosphorylation and L-type calcium current (I(Ca)) facilitation, dependent on compartmental calcium.
  • Kv4.3 overexpression inhibited both basal and calcium-induced CaMKII activation by blocking calmodulin binding sites.

Conclusions:

  • Identified a novel mechanism where I(to) channel subunit Kv4.3 regulates CaMKII activation in cardiomyocytes.
  • Demonstrated that alterations in I(to) channels, specifically Kv4.3 function, are implicated in the pathological overactivation of CaMKII observed in heart failure.
Abstract

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