Targeted deletion of Kv4.2 eliminates Ito,f and results in electrical and molecular remodeling, with no evidence of ventricular hypertrophy or myocardial dysfunction

Previous studies have demonstrated a role for voltage-gated K+ (Kv) channel alpha subunits of the Kv4 subfamily in the generation of rapidly inactivating/recovering cardiac transient outward K+ current, I-to,I- f, channels. Biochemical studies suggest that mouse ventricular Ito, f channels reflect the heteromeric assembly of Kv4.2 and Kv4.3 with the accessory subunits, KChIP2 and Kv beta 1, and that Kv4.2 is the primary determinant of regional differences in ( mouse ventricular) I-to,I- f densities. Interestingly, the phenotypic consequences of manipulating I-to,I- f expression in different mouse models are distinct. In the experiments here, the effects of the targeted deletion of Kv4.2 (Kv4.2(-/-)) were examined. Unexpectedly, voltage-clamp recordings from Kv4.2(-/-) ventricular myocytes revealed that I-to,I- f is eliminated. In addition, the slow transient outward K+ current, I-to,I- s, and the Kv1.4 protein (which encodes I-to,I- s) are upregulated in Kv4.2(-/-) ventricles. Although Kv4.3 mRNA/protein expression is not measurably affected, KChIP2 expression is markedly reduced in Kv4.2(-/-) ventricles. Similar to Kv4.3, expression of Kv beta 1, as well as Kv1.5 and Kv2.1, is similar in wild-type and Kv4.2(-/-) ventricles. In addition, and in marked contrast to previous findings in mice expressing a truncated Kv4.2 transgene, the elimination I-to,I- f in Kv4.2(-/-) mice does not result in ventricular hypertrophy. Taken together, these findings demonstrate not only an essential role for Kv4.2 in the generation of mouse ventricular I-to,I- f channels but also that the loss of I-to,I- f per se does not have overt pathophysiological consequences.