Metabolic regulation of Kv channels and cardiac repolarization by Kvβ2 subunits

Voltage-gated potassium (Kv) channels control myocardial repolarization. Pore-forming Kv alpha proteins associate with intracellular Kv beta subunits, which bind pyridine nucleotides with high affinity and differentially regulate channel trafficking, plasmalemmal localization and gating properties. Nevertheless, it is unclear how Kv beta subunits regulate myocardial K+ currents and repolarization. Here, we tested the hypothesis that Kv beta 2 subunits regulate the expression of myocardial Kv channels and confer redox sensitivity to Kv current and cardiac repolarization. Co-immunoprecipitation and in situ proximity ligation showed that in cardiac myocytes, Kv beta 2 interacts with Kv1.4, Kv1.5, Kv4.2, and Kv4.3. Cardiac myocytes from mice lacking Kcnab2 (Kv beta 2(-/-)) had smaller cross sectional areas, reduced sarcolemmal abundance of Kv alpha binding partners, reduced I-to, I-K,I-slow1, and I-K,I-slow2 densities, and prolonged action potential duration compared with myocytes from wild type mice. These differences in Kv beta 2(-/-) mice were associated with greater P wave duration and QT interval in electrocardiograms, and lower ejection fraction, fractional shortening, and left ventricular mass in echocardiographic and morphological assessments. Direct intracellular dialysis with a high NAD(P)H:NAD(P)(+) accelerated Kv inactivation in wild type, but not Kv beta 2(-/-) myocytes. Furthermore, elevated extracellular levels of lactate increased [NADH](i) and prolonged action potential duration in wild type cardiac myocytes and perfused wild type, but not Kv beta 2(-/-), hearts. Taken together, these results suggest that Kv beta 2 regulates myocardial electrical activity by supporting the functional expression of proteins that generate I-to and I-K,I-slow, and imparting redox and metabolic sensitivity to Kv channels, thereby coupling cardiac repolarization to myocyte metabolism.