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Metabolic regulation of Kv channels and cardiac repolarization by Kv?2 subunits.

ABSTRACT: Voltage-gated potassium (Kv) channels control myocardial repolarization. Pore-forming Kv? proteins associate with intracellular Kv? subunits, which bind pyridine nucleotides with high affinity and differentially regulate channel trafficking, plasmalemmal localization and gating properties. Nevertheless, it is unclear how Kv? subunits regulate myocardial K⁺ currents and repolarization. Here, we tested the hypothesis that Kv?2 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, Kv?2 interacts with Kv1.4, Kv1.5, Kv4.2, and Kv4.3. Cardiac myocytes from mice lacking Kcnab2 (Kv?2^-/-) had smaller cross sectional areas, reduced sarcolemmal abundance of Kv? binding partners, reduced I_to, I_K,slow1, and I_K,slow2 densities, and prolonged action potential duration compared with myocytes from wild type mice. These differences in Kv?2^-/- 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 Kv?2^-/- 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 Kv?2^-/-, hearts. Taken together, these results suggest that Kv?2 regulates myocardial electrical activity by supporting the functional expression of proteins that generate I_to and I_K,slow, and imparting redox and metabolic sensitivity to Kv channels, thereby coupling cardiac repolarization to myocyte metabolism.

SUBMITTER: Kilfoil PJ

PROVIDER: S-EPMC7344177 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Metabolic regulation of Kv channels and cardiac repolarization by Kvβ2 subunits.

Kilfoil Peter J PJ Chapalamadugu Kalyan C KC Hu Xuemei X Zhang Deqing D Raucci Frank J FJ Tur Jared J Brittian Kenneth R KR Jones Steven P SP Bhatnagar Aruni A Tipparaju Srinivas M SM Nystoriak Matthew A MA

Journal of molecular and cellular cardiology 20191019

Voltage-gated potassium (Kv) channels control myocardial repolarization. Pore-forming Kvα proteins associate with intracellular Kvβ subunits, which bind pyridine nucleotides with high affinity and differentially regulate channel trafficking, plasmalemmal localization and gating properties. Nevertheless, it is unclear how Kvβ subunits regulate myocardial K<sup>+</sup> currents and repolarization. Here, we tested the hypothesis that Kvβ2 subunits regulate the expression of myocardial Kv channels a ...[more]

PMID: 31639389

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Dataset Information

Metabolic regulation of Kv channels and cardiac repolarization by Kv?2 subunits.

Publications

Metabolic regulation of Kv channels and cardiac repolarization by Kvβ2 subunits.

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