title: 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.NEW & NOTEWORTHYCardiac 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.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, Florida.|Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida.
authors.forename: Jared
authors.initials: J
authors.lastname: Tur
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, Florida.
authors.forename: Kalyan C
authors.initials: KC
authors.lastname: Chapalamadugu
authors.affiliation: Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, Florida; and.
authors.forename: Christopher
authors.initials: C
authors.lastname: Katnik
authors.affiliation: Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, Florida; and.
authors.forename: Javier
authors.initials: J
authors.lastname: Cuevas
authors.affiliation: Diabetes and Obesity Center, University of Louisville, Louisville, Kentucky.
authors.forename: Aruni
authors.initials: A
authors.lastname: Bhatnagar
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, Florida; stippara@health.usf.edu.
authors.forename: Srinivas M
authors.initials: SM
authors.lastname: Tipparaju
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D055724:Electrophysiological Phenomena / Q000187:drug effects; D006321:Heart / Q000187:drug effects*; D007545:Isoproterenol / Q000494:pharmacology; D051662:Kv1.1 Potassium Channel / Q000378:metabolism*; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism*; D009243:NAD / Q000378:metabolism; D009711:Nucleotides / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D011725:Pyridines / Q000378:metabolism*; D051381:Rats; D051672:Shal Potassium Channels
chemical_list: D000318:Adrenergic beta-Agonists; D009711:Nucleotides; D011725:Pyridines; D051672:Shal Potassium Channels; D009243:NAD; D051662:Kv1.1 Potassium Channel; D019344:Lactic Acid; D007545:Isoproterenol
keywords: Kvβ subunit; aldo-keto reductase; heart; potassium channel; pyridine nucleotides; redox