Molecular basis of transient outward K+ current diversity in mouse ventricular myocytes.

1. Two kinetically and pharmacologically distinct transient outward K+ currents, referred to as Ito,f and Ito,s, have been distinguished in mouse left ventricular myocytes. Ito,f is present in all left ventricular apex cells and in most left ventricular septum cells, whereas Ito,s is identified exclusively in left ventricular septum cells. 2. Electrophysiological recordings from ventricular myocytes isolated from animals with a targeted deletion of the Kv1.4 gene (Kv1.4-/- mice) reveal that Ito,s is undetectable in cells isolated from the left ventricular septum (n = 26). Ito,f density in both apex and septum cells, in contrast, is not affected by deletion of Kv1.4. 3. Neither the 4-AP-sensitive, slowly inactivating K+ current, IK,slow, nor the steady-state non-inactivating K+ current, ISS, is affected in Kv1.4-/- mouse left ventricular cells. 4. In myocytes isolated from transgenic mice expressing a dominant negative Kv4.2 alpha subunit, Kv4.2W362F, Ito,f is eliminated in both left ventricular apex and septum cells. In addition, a slowly inactivating transient outward K+ current similar to Ito,s in wild-type septum cells is evident in myocytes isolated from left ventricular apex of Kv4.2W362F-expressing transgenics. The density of Ito,s in septum cells, however, is unaffected by Kv4.2W362F expression. 5. Western blots of fractionated mouse ventricular membrane proteins reveal a significant increase in Kv1.4 protein level in Kv4.2W362F-expressing transgenic mice. The protein levels of other Kv alpha subunits, Kv1.2 and Kv2.1, in contrast, are not affected by the expression of the Kv4.2W362F transgene. 6. The results presented here demonstrate that the molecular correlates of Ito,f and Ito,s in adult mouse ventricle are distinct. Kv1.4 underlies mouse ventricular septum Ito,s, whereas Kv alpha subunits of the Kv4 subfamily underlie mouse ventricular apex and septum Ito, f. The appearance of the slow transient outward K+ current in Kv4. 2W362F-expressing left ventricular apex cells with properties indistinguishable from Ito,s in wild-type cells is accompanied by an increase in Kv1.4 protein expression, suggesting that the upregulation of Kv1.4 underlies the observed electrical remodeling in Kv4.2W362F-expressing transgenics.