| First Author | Tur J | Year | 2017 |
| Journal | Am J Physiol Heart Circ Physiol | Volume | 312 |
| Issue | 3 | Pages | H571-H583 |
| PubMed ID | 27986658 | Mgi Jnum | J:240115 |
| Mgi Id | MGI:5882443 | Doi | 10.1152/ajpheart.00281.2016 |
| Citation | Tur J, et al. (2017) Kvbeta1.1 (AKR6A8) senses pyridine nucleotide changes in the mouse heart and modulates cardiac electrical activity. Am J Physiol Heart Circ Physiol 312(3):H571-H583 |
| abstractText | The present study investigates the physiological role of Kvbeta1 subunit for sensing pyridine nucleotide (NADH/NAD+) changes in the heart. We used Kvbeta1.1 knockout (KO) or wild-type (WT) mice and established that Kvbeta1.1 preferentially binds with Kv4.2 and senses the pyridine nucleotide changes in the heart. The cellular action potential duration (APD) obtained from WT cardiomyocytes showed longer APDs with lactate perfusion, which increases intracellular NADH levels, while the APDs remained unaltered in the Kvbeta1.1 KO. Ex vivo monophasic action potentials showed a similar response, in which the APDs were prolonged in WT mouse hearts with lactate perfusion; however, the Kvbeta1.1 KO mouse hearts did not show APD changes upon lactate perfusion. COS-7 cells coexpressing Kv4.2 and Kvbeta1.1 were used for whole cell patch-clamp recordings to evaluate changes caused by NADH (lactate). These data reveal that Kvbeta1.1 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 wild-type mice; regardless of the approach, our data show that Kvbeta1.1 recognizes NADH changes and modulates Kv4.2 currents affecting AP and QTc durations. Overall, this study uses multiple levels of investigation, including the heterologous overexpression system, cardiomyocyte, ex vivo, and ECG, and clearly depicts that Kvbeta1.1 is an obligatory sensor of NADH/NAD changes in vivo, with a physiological role in the heart.NEW & NOTEWORTHY Cardiac electrical activity is mediated by ion channels, and Kv4.2 plays a significant role, along with its binding partner, the Kvbeta1.1 subunit. In the present study, we identify Kvbeta1.1 as a sensor of pyridine nucleotide changes and as a modulator of Kv4.2 gating, action potential duration, and ECG in the mouse heart. |
