Stabilization of Kv4 protein by the accessory K⁺ channel interacting protein 2 (KChIP2) subunit is required for the generation of native myocardial fast transient outward K⁺ currents

The fast transient outward K⁺ current (I_to,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 I_to,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 I_to,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 I_to,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 I_to,f in KChIP2^-/- ventricular myocytes. In parallel with the elimination of I_to,f, the slow transient outward K⁺ current (I_to,s) is upregulated and voltage-gated Ca²⁺ currents (I_Ca,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 I_to,s and the reduction in I_Ca,L compensate for the loss of I_to,f. Additional experiments revealed that I_to,f is not 'rescued' by adenovirus-mediated expression of KChIP2 in KChIP2^-/- myocytes, although I_Ca,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 I_to,f channel expression.