Kv4.3-Encoded Fast Transient Outward Current Is Presented in Kv4.2 Knockout Mouse Cardiomyocytes

Gradients of the fast transient outward K(+) current (I(to,f)) contribute to heterogeneity of ventricular repolarization in a number of species. Cardiac I(to,f) levels and gradients change notably with heart disease. Human cardiac I(to,f) appears to be encoded by the Kv4.3 pore-forming α-subunit plus the auxiliary KChIP2 β-subunit while mouse cardiac I(to,f) requires Kv4.2 and Kv4.3 α-subunits plus KChIP2. Regional differences in cardiac I(to,f) are associated with expression differences in Kv4.2 and KChIP2. Although I(to,f) was reported to be absent in mouse ventricular cardiomyocytes lacking the Kv4.2 gene (Kv4.2-/-) when short depolarizing voltage pulses were used to activate voltage-gated K(+) currents, in the present study, we showed that the use of long depolarization steps revealed a heteropodatoxin-sensitive I(to,f) (at ~40% of the wild-type levels). Immunohistological studies further demonstrated membrane expression of Kv4.3 in Kv4.2-/- cardiomyocytes. Transmural I(to,f) gradients across the left ventricular wall were reduced by ~3.5-fold in Kv4.2-/- heart, compared to wild-type. The I(to,f) gradient in Kv4.2-/- hearts was associated with gradients in KChIP2 mRNA expression while in wild-type there was also a gradient in Kv4.2 expression. In conclusion, we found that Kv4.3-based I(to,f) exists in the absence of Kv4.2, although with a reduced transmural gradient. Kv4.2-/- mice may be a useful animal model for studying Kv4.3-based I(to,f) as observed in humans.