Deletion in mice of X-linked, Brugada syndrome- and atrial fibrillation-associated Kcne5 augments ventricular K V 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,f ). The current increases arose from an apex-specific increase in slow transient outward current-1 ( I _Kslow,1 ) (conducted by K _V 1.5) and I _to,f (conducted by K _V 4) and an increase in I _Kslow,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,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.