Deletion in mice of X-linked, Brugada syndrome- and atrial fibrillation-associated Kcne5 augments ventricular KV currents and predisposes to ventricular arrhythmia

KCNE5 is an X-linked gene encoding KCNE5, an ancillary subunit to voltage-gated potassium (K-V) channels. Human KCNE5 mutations are associated with atrial fibrillation (AF)- and Brugada syndrome (BrS)-induced cardiac arrhythmias that can arise from increased potassium current in cardiomyocytes. Seeking to establish underlying molecular mechanisms, we created and studied Kcne5 knockout (Kcne5(-/0)) mice. Intracardiac ECG revealed that Kcne5 deletion caused ventricular premature beats, increased susceptibility to induction of polymorphic ventricular tachycardia (60 vs. 24% in Kcne5(+/0) mice), and 10% shorter ventricular refractory period. Kcne5 deletion increased mean ventricular myocyte K-V current density in the apex and also in the subpopulation of septal myocytes that lack fast transient outward current (I-to,I-f). The current increases arose from an apex-specific increase in slow transient outward current-1 (I-Kslow,I-1) (conducted by K(V)1.5) and I-to,I-f (conducted by K(V)4) and an increase in I-Kslow,I-2 (conducted by K(V)2.1) in both apex and septum. Kcne5 protein localized to the intercalated discs in ventricular myocytes, where K(V)2.1 was also detected in both Kcne5(-/0) and Kcne5(+/0) mice. In HL-1 cardiac cells and human embryonic kidney cells, KCNE5 and K(V)2.1 colocalized at the cell surface, but predominantly in intracellular vesicles, suggesting that Kcne5 deletion increases I-K,I-slow2 by reducing K(V)2.1 intracellular sequestration. The human AF-associated mutation KCNE5-L65F negative shifted the voltage dependence of K(V)2.1-KCNE5 channels, increasing their maximum current density >2-fold, whereas BrS-associated KCNE5 mutations produced more subtle negative shifts in K(V)2.1 voltage dependence. The findings represent the first reported native role for Kcne5 and the first demonstrated Kcne regulation of K(V)2.1 in mouse heart. Increased K-V current is a manifestation of KCNE5 disruption that is most likely common to both mouse and human hearts, providing a plausible mechanistic basis for human KCNE5-linked AF and BrS.David, J.-P., Lisewski, U., Crump, S. M., Jepps, T. A., Bocksteins, E., Wilck, N., Lossie, J., Roepke, T. K., Schmitt, N., Abbott, G. W. Deletion in mice of X-linked, Brugada syndrome- and atrial fibrillation-associated Kcne5 augments ventricular K-V currents and predisposes to ventricular arrhythmia.