Modulation of the cardiac sodium channel Nav1.5 peak and late currents by NAD+ precursors
Matasic D, Yoon JY, McLendon JM, Mehdi H, Schmidt MS, Greiner AM, Quinones P, Morgan GM, Boudreau RL, Irani K, Brenner C, London B
Journal
Journal of Molecular and Cellular Cardiology
Model
Mouse
Impact Factor
5.296
Rationale
The cardiac sodium channel Na V1.5, encoded by SCN5A, produces the rapidly inactivating depolarizing current I Na that is responsible for the initiation and propagation of the cardiac action potential. Acquired and inherited dysfunction of Na V1.5 results in either decreased peak I Na or increased residual late I Na (I Na,L), leading to tachy/bradyarrhythmias and sudden cardiac death. Previous studies have shown that increased cellular NAD + and NAD +/NADH ratio increase I Na through suppression of mitochondrial reactive oxygen species and PKC-mediated Na V1.5 phosphorylation. In addition, NAD +-dependent deacetylation of Na V1.5 at K1479 by Sirtuin 1 increases Na V1.5 membrane trafficking and I Na. The role of NAD + precursors in modulating I Na remains unknown.
Objective
To determine whether and by which mechanisms the NAD + precursors nicotinamide riboside (NR) and nicotinamide (NAM) affect peak I Na and I Na,L in vitro and cardiac electrophysiology in vivo.
Methods/Results
The effects of NAD + precursors on the NAD + metabolome and electrophysiology were studied using HEK293 cells expressing wild-type and mutant Na V1.5, rat neonatal cardiomyocytes (RNCMs), and mice. NR increased I Na in HEK293 cells expressing Na V1.5 (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 I Na,L at the higher concentration (RNCMs, 5 mM: −45 ± 11%, p = .04). NR (5 mM) decreased Na V1.5 K1479 acetylation but increased I Na in HEK293 cells expressing a mutant form of Na V1.5 with disruption of the acetylation site (Na V1.5-K1479A). Disruption of the PKC phosphorylation site abolished the effect of NR on I Na. Furthermore, NAM (5 mM) had no effect on I Na in RNCMs or in HEK293 cells expressing wild-type Na V1.5, but increased I Na in HEK293 cells expressing Na V1.5-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).
Conclusions
NAD + precursors differentially regulate Na V1.5 via multiple mechanisms. NR increases I Na, decreases I Na,L, and warrants further investigation as a potential therapy for arrhythmic disorders caused by Na V1.5 deficiency and/or dysfunction.
Keywords
Cardiac Sodium Channel (NaV1.5, SCN5A), Arrhythmia, Metabolic regulation, NAD+/NADH, Nicotinamide riboside, Nicotinamide, Sirtuins, Acetylation