The present study investigates the physiological role of Kvβ1 subunit for sensing pyridine nucleotide (NADH/NAD+) changes in the heart. We utilized Kvβ1.1 knockout or wild type mice and established that Kvβ1.1 preferentially binds with Kv4.2 and senses the pyridine nucleotide changes in the heart. The cellular action potential duration (APD) obtained from wild type cardiomyocytes showed longer APD's with lactate perfusion which increases intracellular NADH levels, while the APD's remained unaltered in the Kvβ1.1 KO. Ex vivo monophasic action potentials showed similar response in which the APD's were prolonged in wild type mouse hearts with lactate perfusion, however the Kvβ1.1 KO mouse hearts did not show APD changes upon lactate perfusion. COS-7 cells co-expressing Kv4.2 and Kvβ1.1 were utilized for whole-cell patch-clamp recordings to evaluate changes caused by NADH (lactate). These data reveal that Kvβ1.1 is required in the mediated inactivation of Kv4.2 currents when NADH (lactate) levels are increased. In vivo, isoproterenol infusion led to increased NADH in the heart along with QTc prolongation in WT, regardless of the approach our data show that Kvβ1.1 recognizes NADH changes and modulates Kv4.2 currents affecting AP and QTc durations. Overall, this study utilizes multiple levels of investigation including the heterologous overexpression system, cardiomyocyte, ex vivo and ECG, clearly depicting that Kvβ1.1 is an obligatory sensor of NADH/NAD changes in vivo with a physiological role in the heart.
- Kvβ subunit
- pyridine nucleotides
- potassium channel
- Copyright © 2016, American Journal of Physiology-Heart and Circulatory Physiology