Metabolic regulation of Kv channels and cardiac repolarization by Kvβ2 subunits

• Published in: Journal of molecular and cellular cardiology 2019-12, Vol.137, p.93-106
• Main Authors: Kilfoil, Peter J., Chapalamadugu, Kalyan C., Hu, Xuemei, Zhang, Deqing, Raucci, Frank J., Tur, Jared, Brittian, Kenneth R., Jones, Steven P., Bhatnagar, Aruni, Tipparaju, Srinivas M., Nystoriak, Matthew A.
• Format: Article
• Language: English
• Subjects: Arrhythmia; Heart; Metabolism; NAD; Redox
• ISSN: 0022-2828; 1095-8584
• DOI: 10.1016/j.yjmcc.2019.09.013

Voltage-gated potassium (Kv) channels control myocardial repolarization. Pore-forming Kvα proteins associate with intracellular Kvβ subunits, which bind pyridine nucleotides with high affinity and differentially regulate channel trafficking, plasmalemmal localization and gating properties. Nevertheless, it is unclear how Kvβ subunits regulate myocardial K+ currents and repolarization. Here, we tested the hypothesis that Kvβ2 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, Kvβ2 interacts with Kv1.4, Kv1.5, Kv4.2, and Kv4.3. Cardiac myocytes from mice lacking Kcnab2 (Kvβ2−/−) had smaller cross sectional areas, reduced sarcolemmal abundance of Kvα binding partners, reduced Ito, IK,slow1, and IK,slow2 densities, and prolonged action potential duration compared with myocytes from wild type mice. These differences in Kvβ2−/− 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 Kvβ2−/− 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 Kvβ2−/−, hearts. Taken together, these results suggest that Kvβ2 regulates myocardial electrical activity by supporting the functional expression of proteins that generate Ito and IK,slow, and imparting redox and metabolic sensitivity to Kv channels, thereby coupling cardiac repolarization to myocyte metabolism. •Kv auxiliary Kvβ2 subunits interact with Kv1 and Kv4 channels in the murine heart.•Ablation of Kvβ2 leads to suppression of Ito, IK,slow1 and IK,slow2, and prolongs action potential duration.•Pyridine nucleotide ratios simulating hypoxic conditions enhance Kv inactivation in wild type, but not Kvβ2−/− myocytes.•Lactate increases NADH:NAD+ ratio and prolongs action potential duration in wild type, but not Kvβ2−/− hearts.