Kvβ1.1 (AKR6A8) senses pyridine nucleotide changes in the mouse heart and modulates cardiac electrical activity

Abstract

The present study investigates the physiological role of Kvβ1 subunit for sensing pyridine nucleotide (NADH/NAD+) changes in the heart. We used Kvβ1.1 knockout (KO) or wild-type (WT) 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 WT cardiomyocytes showed longer APDs with lactate perfusion, which increases intracellular NADH levels, while the APDs remained unaltered in the Kvβ1.1 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 Kvβ1.1 KO mouse hearts did not show APD changes upon lactate perfusion. COS-7 cells coexpressing Kv4.2 and Kvβ1.1 were used 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 wild-type mice; 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 uses multiple levels of investigation, including the heterologous overexpression system, cardiomyocyte, ex vivo, and ECG, and clearly depicts that Kvβ1.1 is an obligatory sensor of NADH/NAD changes in vivo, with a physiological role in the heart. Cardiac electrical activity is mediated by ion channels, and Kv4.2 plays a significant role, along with its binding partner, the Kvβ1.1 subunit. In the present study, we identify Kvβ1.1 as a sensor of pyridine nucleotide changes and as a modulator of Kv4.2 gating, action potential duration, and ECG in the mouse heart.

Corticosteroids and aldose reductase inhibitor Epalrestat modulates cardiac action potential via Kvβ1.1 (AKR6A8) subunit of voltage-gated potassium channel

“…Mice were obtained from Jackson Laboratories (Bar Harbor, ME, USA); Kvβ1.1 KO (global knockout) and control or WT mice (C57BL/6NJ)[7]. Mice 14–16 weeks of age (Males) were provided water and food ad libitum .…”

“…Monophasic action potentials (MAPs) were recorded from ex vivo heart preparations as reported before [7, 15]. Briefly, 1 mg heparin (180 USP, Sigma-Aldrich, St. Louis, MO, USA) was injected into the mice following euthanizing with Somnasol (Pentobarbital Sodium, 50 mg (kg body weight), Henry Schein Animal Health, Dublin, OH, USA) by i.p.…”

“…The Kvβ subunits represent a unique class of aldoketo reductases (AKR) which bind and alter many different voltage-gated potassium channels (Kv) [6, 7]. Recently we demonstrated that global knockout of Kvβ1.1 in mouse resulted in significant prolongation of monophasic action potential as well at QTc [8].…”

“…Further, we also demonstrated that the binding of pyridine nucleotide to Kvβ1.1 subunits can modulate the gating potential of Kv4.2 a key player in the I to current responsible for the initial phase of the repolarization in cardiac action potentials. The addition of lactate resulted in significant increase in intracellular NADH and led to increased rates of Kv4.2 inactivation cardiac action potential prolongation [7]. Therefore, we hypothesized that Kvβ1.1 can interact with cortisone and other ligands and regulate the cardiac action potential.…”

Emerging potential benefits of modulating NAD+metabolism in cardiovascular disease

“…Additionally, K ϩ voltage-gated channel subfamily D member 2 (K v 4.2), a voltage-gated K ϩ channel that contributes to the transient outward potassium repolarization current, is subject to modulation by NAD ϩ /NADH through its pyridinesensing K v ␤1.1 ␤-subunit (96). In the presence of K v ␤1.1, K v 4.2 demonstrates an inactivation in heterologous cell systems that would mitigate the repolarization current and prolong the action potential.…”