Logo image
Back
Modulation of the cardiac sodium channel NaV1.5 peak and late currents by NAD+ precursors
Journal article   Peer reviewed

Modulation of the cardiac sodium channel NaV1.5 peak and late currents by NAD+ precursors

Daniel S Matasic, Jin-Young Yoon, Jared M McLendon, Haider Mehdi, Mark S Schmidt, Alexander M Greiner, Pravda Quinones, Gina M Morgan, Ryan L Boudreau, Kaikobad Irani, …
Journal of molecular and cellular cardiology, Vol.141, pp.70-81
04/2020
DOI: 10.1016/j.yjmcc.2020.01.013
PMID: 32209328
url
https://www.ncbi.nlm.nih.gov/pmc/articles/7234910View
Open Access

Abstract

The cardiac sodium channel NaV1.5, encoded by SCN5A, produces the rapidly inactivating depolarizing current INa that is responsible for the initiation and propagation of the cardiac action potential. Acquired and inherited dysfunction of NaV1.5 results in either decreased peak INa or increased residual late INa (INa,L), leading to tachy/bradyarrhythmias and sudden cardiac death. Previous studies have shown that increased cellular NAD+ and NAD+/NADH ratio increase INa through suppression of mitochondrial reactive oxygen species and PKC-mediated NaV1.5 phosphorylation. In addition, NAD+-dependent deacetylation of NaV1.5 at K1479 by Sirtuin 1 increases NaV1.5 membrane trafficking and INa. The role of NAD+ precursors in modulating INa remains unknown. To determine whether and by which mechanisms the NAD+ precursors nicotinamide riboside (NR) and nicotinamide (NAM) affect peak INa and INa,Lin vitro and cardiac electrophysiology in vivo. The effects of NAD+ precursors on the NAD+ metabolome and electrophysiology were studied using HEK293 cells expressing wild-type and mutant NaV1.5, rat neonatal cardiomyocytes (RNCMs), and mice. NR increased INa in HEK293 cells expressing NaV1.5 (500 μM: 51 ± 18%, p = .02, 5 mM: 59 ± 22%, p = .03) and RNCMs (500 μM: 60 ± 26%, p = .02, 5 mM: 74 ± 39%, p = .03) while reducing INa,L at the higher concentration (RNCMs, 5 mM: −45 ± 11%, p = .04). NR (5 mM) decreased NaV1.5 K1479 acetylation but increased INa in HEK293 cells expressing a mutant form of NaV1.5 with disruption of the acetylation site (NaV1.5-K1479A). Disruption of the PKC phosphorylation site abolished the effect of NR on INa. Furthermore, NAM (5 mM) had no effect on INa in RNCMs or in HEK293 cells expressing wild-type NaV1.5, but increased INa in HEK293 cells expressing NaV1.5-K1479A. Dietary supplementation with NR for 10–12 weeks decreased QTc in C57BL/6 J mice (0.35% NR: −4.9 ± 2.0%, p = .14; 1.0% NR: −9.5 ± 2.8%, p = .01). NAD+ precursors differentially regulate NaV1.5 via multiple mechanisms. NR increases INa, decreases INa,L, and warrants further investigation as a potential therapy for arrhythmic disorders caused by NaV1.5 deficiency and/or dysfunction. •The NAD+ precursor Nicotinamide Riboside (NR) increases peak sodium current (INa) and reduces late INa.•NR decreases Nav1.5 K1479 deacetylation.•The effect of NR on increasing INa is mediated through the PKC-dependent phosphorylation site S1503.•Nicotinamide (NAM) has differential effects on peak INa which are dependent on the Sirtuin-dependent acetylation-site K1479.•Dietary NR supplementation reduced QTc in C57BL/6 mice, consistent with a decrease in INa,L.
 Sirtuins Arrhythmia NAD+/NADH Cardiac Sodium Channel (NaV1.5, SCN5A) Metabolic regulation Nicotinamide Acetylation Nicotinamide riboside

Details

Metrics

35 Record Views
15 Times Cited - Web of Science
Logo image