Potential molecular basis of different physiological properties of the transient outward K+ current in rabbit and human atrial myocytes.

The properties of the transient outward current (Ito) differ between rabbit and human atrial myocytes. In particular, rabbit Ito is known to recover more slowly than its human counterpart and to show much more frequency dependence. To assess the possibility that these physiological differences may reflect differing expression of K+ channel subunit gene products, we used a combination of whole-cell voltage-clamp, heterologous expression, pharmacological, antisense, and Western blot techniques. The inactivation of Ito in rabbit atrial myocytes was significantly slowed by hydrogen peroxide, with human Ito being unaffected. Use-dependent unblocking with 4-aminopyridine was not seen for rabbit Ito nor for Kv1.4 currents in Xenopus oocytes, whereas human Ito showed strong use-dependent unblock (as did Kv4 currents). Western blots indicated the presence of Kv4 proteins in both human and rabbit atrial membranes, but Kv1.4 was only detected in the rabbit. Antisense oligodeoxynucleotides directed against Kv4.3, Kv4.2, or Kv1.4 subunit sequences significantly inhibited Ito current density in cultured rabbit atrial myocytes, whereas only Kv4.3 antisense significantly inhibited Ito in human cells. Neither mismatch oligodeoxynucleotides nor vehicle altered currents in either species. We conclude that, unlike human atrial myocytes, rabbit atrial myocytes express Kv1.4 channel subunits, which likely contribute to a number of important physiological differences in Ito properties between the species. To our knowledge, these studies constitute the first demonstration of a functional role for Kv1.4 channels in cardiac membranes and provide insights into the molecular mechanisms of an important cardiac repolarizing current.