Abstract Body: Introduction: Cardiac fast transient outward potassium currents (I_to,f) are formed by KCND2 (Kv4.2) and KCND3 (Kv4.3) channels in mice and primarily KCND3 in humans. Rapid I_to,f activation induces early phase 1 repolarization of action potentials (APs), which has been linked strongly to the modulation of excitation-contraction coupling (ECC). Consequently, variations in I_to,f densities underlie regional differences in ventricular APs and myocardial contractile properties. To investigate further the role of I_to,f in cardiac function, we created mice with fluorescently labelled KCND2 (KCND2-GFP) and KCND3 (KCND3-RFP).

Methods and Results: The expression patterns of I_to,f in the ventricles were examined using frozen histological sections. Remarkably, KCND2 and KCND3 were preferentially localized to the intercalated discs (ICDs) by >50%, with expression also in lateral membranes and within t-tubules (i.e. a sarcomeric pattern), yet KCND3 showed a greater t-tubule localization. Additionally, KCND2 expression was, as expected, greater (P<0.048, two-way ANOVA; n=3) in the epi- versus endo-myocardium of both ventricles, whereas KCND3 lacked (P>0.172; n=3) a distinct gradient. Moreover, KCND2 expression inversely correlated with the temporal sequence of ventricular activation, whereby the posterobasal regions that depolarize last show elevated Kv4.2 (P=0.009, unpaired t-test; n=3) compared to the anterolateral endocardium activated first. In contrast, Kv4.3 demonstrates a relatively uniform expression.

Conclusions: The regional expression patterns of I_to,f in ventricles and preferential I_to,f expression in t-tubules support previous studies suggesting that I_to,f controls the regional variations in the timing and amplitude of ECC. We are currently exploring the possible differential actions of KCND2 versus KCND3 in ECC and the potential consequence of ICD localization of I_to,f on ephaptic coupling.