Elimination of the transient outward current and action potential prolongation in mouse atrial myocytes expressing a dominant negative Kv4 α subunit

Abstract

Analyses of whole-cell voltage-clamp recordings from isolated adult (C57BL6) mouse atrial myocytes reveal the presence of two prominent Ca2+-independent depolarization-activated K+ currents: a rapidly activating and inactivating, transient outward K+ current, Ito,f; and a non-inactivating, steady-state, K+ current, Iss. The properties of Ito,f and Iss in adult mouse atrial myocytes are similar to those of the analogous currents recently described in detail in adult mouse ventricular cells. A slowly inactivating K+ current, which is similar to IK,slow in ventricular cells, is detected in ≈40 % of adult mouse atrial myocytes, and when expressed, the density of this current component is substantially lower than the density of Ito,f or Iss. The similarity between atrial and ventricular Ito,f and the finding that both the Kv4 subfamily α subunits, Kv4.2 and Kv4.3, are expressed in wild-type mouse atria prompted us to determine if atrial Ito,f is affected in transgenic mice expressing a mutant Kv4.2 α subunit, Kv4.2W362F, that functions as a dominant negative. Similar to findings in ventricular cells, electrophysiological recordings reveal that Ito,f is selectively eliminated in atrial myocytes isolated from transgenic mice expressing Kv4.2W362F, thereby demonstrating directly that Kv4 subfamily members also underlie mouse atrial Ito,f. Neither the steady-state, non-inactivating K+ current Iss, nor the inwardly rectifying K+ current IK1, in atrial myocytes is affected by the expression of Kv4.2W362F. In contrast to previous findings in Kv4.2W362F-expressing mouse ventricular myocytes, there is no evidence that electrical remodelling occurs in atrial cells when Ito,f is functionally eliminated. The elimination of Ito,f is accompanied by marked increases in atrial action potential durations, although no electrocardiographic abnormalities attributable to, or suggestive of, altered atrial functioning are evident in Kv4.2W362F-expressing animals.