Targeted Deletion of Kv4.2 Eliminates I to,f and Results in Electrical and Molecular Remodeling, With No Evidence of Ventricular Hypertrophy or Myocardial Dysfunction

Abstract

Previous studies have demonstrated a role for voltage-gated K + (Kv) channel α subunits of the Kv4 subfamily in the generation of rapidly inactivating/recovering cardiac transient outward K + current, I to,f , channels. Biochemical studies suggest that mouse ventricular I to,f channels reflect the heteromeric assembly of Kv4.2 and Kv4.3 with the accessory subunits, KChIP2 and Kvβ1, and that Kv4.2 is the primary determinant of regional differences in (mouse ventricular) I to,f densities. Interestingly, the phenotypic consequences of manipulating I to,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,f is eliminated. In addition, the slow transient outward K + current, I to,s , and the Kv1.4 protein (which encodes I to,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 Kvβ1, 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,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,f channels but also that the loss of I to,f per se does not have overt pathophysiological consequences.