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

1. Two kinetically and pharmacologically distinct transient outward K+ curr ents, referred to as I-to,I-f and I-to,I-s have been distinguished in mouse left ventricular myocytes. I-to,I-f is present in all left ventricular ape x cells and in most left ventricular septum cells, whereas I-to,I-s is iden tified 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 I-to,I-s is undetectable in cells isolated from the left ventricular septum (n = 26). I-to,I-f density in both apex and septum cells, in contras t, is not affected by deletion of Kv1.4. 3. Neither the 4-AP-sensitive, slowly inactivating K+ current, I-K,I-slow, nor the steady-state noninactivating K+ current, I-SS, 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, I-to,I-f is eliminated in both left ventr icular apex and septum cells. In addition, a slowly inactivating transient outward K+ current similar to I-to,I-s in wild-type septum cells is evident in myocytes isolated from left ventricular apex of Kv4.2W362F-expressing t ransgenics. The density of I-to,I-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 tra nsgenic 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 transg ene. 6. The results presented here demonstrate that the molecular correlates of I-to,I-f and I-to,I-s in adult mouse ventricle are distinct. Kv1.4 underlie s mouse ventricular septum I-to,I-s, whereas Ky a subunits of the Kv4 subfa mily underlie mouse ventricular apex and septum I-to,I-f. The appearance of the slow transient outward K+ current in Kv4.2W362P-expressing left ventri cular apex cells with properties indistinguishable from I-to,I-s in wild-ty pe cells is accompanied by an increase in Kv1.4 protein expression, suggest ing that the upregulation of Kv1.4 underlies the observed electrical remode ling in Kv4.2W362F-expressing transgenics.