Role of Heteromultimers in the Generation of Myocardial Transient Outward K + Currents

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Abstract
Previous studies have demonstrated a role for Kv4 α subunits in the generation of the fast transient outward K+ current, Ito,f, in the mammalian myocardium. The experiments here were undertaken to explore the role of homomeric/heteromeric assembly of Kv4.2 and Kv4.3 and of the Kv channel accessory subunit, KChIP2, in the generation of mouse ventricular Ito,f. Western blots reveal that the expression of Kv4.2 parallels the regional heterogeneity in Ito,f density, whereas Kv4.3 and KChIP2 are uniformly expressed in adult mouse ventricles. Antisense oligodeoxynucleotides (AsODNs) targeted against Kv4.2 or Kv4.3 selectively attenuate Ito,f in mouse ventricular cells. Adenoviral-mediated coexpression of Kv4.2 and Kv4.3 in HEK-293 cells and in mouse ventricular myocytes produces transient outward K+ currents with properties distinct from those produced on expression of Kv4.2 or Kv4.3 alone, and the gating properties of the heteromeric Kv4.2/Kv4.3 channels in ventricular cells are more similar to native Ito,f than are the homomeric Kv4.2 or Kv4.3 channels. Biochemical studies reveal that Kv4.2, Kv4.3, and KChIP2 coimmunoprecipitate from adult mouse ventricles. In addition, most of the Kv4.2 and KChIP2 are associated with Kv4.3 in situ. Taken together, these results demonstrate that functional mouse ventricular Ito,f channels are heteromeric, comprising Kv4.2/Kv4.3 α subunits and KChIP2. The results here also suggest that Kv4.2 is the primary determinant of the regional heterogeneity in Ito,f expression in adult mouse ventricle.