SEARCH

SEARCH BY CITATION

Key points

  • • 
    The cytosolic K+ channel accessory subunit, K+ channel interacting protein 2 (KChIP2), was previously suggested to be critical in the generation of cardiac fast transient outward current (Ito,f) channels.
  • • 
    The experiments presented here revealed the novel finding that targeted deletion of KChIP2 results in the complete loss of the Kv4.2 protein, although Kcnd2 (Kv4.2) transcript expression is not decreased in KChIP2−/− ventricles.
  • • 
    In contrast, the slow transient outward current, Ito,s, is increased in KChIP2−/− left ventricular apex myocytes and ventricular action potential waveforms in KChIP2−/− and WT mice are not significantly different.
  • • 
    These results demonstrate the critical role of KChIP2 in the stabilization of native Kv4 proteins and that the loss of the Kv4.2 protein underlies the elimination of Ito,f in KChIP2−/− myocytes.
  • • 
    Taken together, the results here demonstrate that electrical remodelling compensates for the elimination of Ito,f, maintaining physiological action potential repolarization in mouse myocardium.

Abstract  The fast transient outward K+ current (Ito,f) underlies the early phase of myocardial action potential repolarization, contributing importantly to the coordinated propagation of activity in the heart and to the generation of normal cardiac rhythms. Native Ito,f channels reflect the tetrameric assembly of Kv4 pore-forming (α) subunits, and previous studies suggest roles for accessory and regulatory proteins in controlling the cell surface expression and the biophysical properties of Kv4-encoded Ito,f channels. Here, we demonstrate that the targeted deletion of the cytosolic accessory subunit, K+ channel interacting protein 2 (KChIP2), results in the complete loss of the Kv4.2 protein, the α subunit critical for the generation of mouse ventricular Ito,f. Expression of the Kcnd2 (Kv4.2) transcript in KChIP2−/− ventricles, however, is unaffected. The loss of the Kv4.2 protein results in the elimination of Ito,f in KChIP2−/− ventricular myocytes. In parallel with the elimination of Ito,f, the slow transient outward K+ current (Ito,s) is upregulated and voltage-gated Ca2+ currents (ICa,L) are decreased. In addition, surface electrocardiograms and ventricular action potential waveforms in KChIP2−/− and wild-type mice are not significantly different, suggesting that the upregulation of Ito,s and the reduction in ICa,L compensate for the loss of Ito,f. Additional experiments revealed that Ito,f is not ‘rescued’ by adenovirus-mediated expression of KChIP2 in KChIP2−/− myocytes, although ICa,L densities are increased. Taken together, these results demonstrate that association with KChIP2 early in the biosynthetic pathway and KChIP2-mediated stabilization of Kv4 protein are critical determinants of native cardiac Ito,f channel expression.