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

Nicholas C. Foeger, Wei Wang, Rebecca L. Mellor, Jeanne M. Nerbonne

Research output: Contribution to journalArticle

29 Scopus citations

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.

Original languageEnglish
Pages (from-to)4149-4166
Number of pages18
JournalJournal of Physiology
Volume591
Issue number17
DOIs
StatePublished - Sep 1 2013

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