| First Author | Kilfoil PJ | Year | 2019 |
| Journal | J Mol Cell Cardiol | Volume | 137 |
| Pages | 93-106 | PubMed ID | 31639389 |
| Mgi Jnum | J:294614 | Mgi Id | MGI:6451288 |
| Doi | 10.1016/j.yjmcc.2019.09.013 | Citation | Kilfoil PJ, et al. (2019) Metabolic regulation of Kv channels and cardiac repolarization by Kvbeta2 subunits. J Mol Cell Cardiol 137:93-106 |
| abstractText | Voltage-gated potassium (Kv) channels control myocardial repolarization. Pore-forming Kvalpha proteins associate with intracellular Kvbeta subunits, which bind pyridine nucleotides with high affinity and differentially regulate channel trafficking, plasmalemmal localization and gating properties. Nevertheless, it is unclear how Kvbeta subunits regulate myocardial K(+) currents and repolarization. Here, we tested the hypothesis that Kvbeta2 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, Kvbeta2 interacts with Kv1.4, Kv1.5, Kv4.2, and Kv4.3. Cardiac myocytes from mice lacking Kcnab2 (Kvbeta2(-/-)) had smaller cross sectional areas, reduced sarcolemmal abundance of Kvalpha 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 Kvbeta2(-/-) 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 Kvbeta2(-/-) 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 Kvbeta2(-/-), hearts. Taken together, these results suggest that Kvbeta2 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. |
