{"doi":"10.1101/2020.02.20.958066","title":"Modulation of the Cardiac Sodium Channel Na <sub>V</sub> 1.5 Peak and Late Currents by NAD <sup>+</sup> Precursors","abstract":"ABSTRACT Rationale The cardiac sodium channel Na V 1.5, 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 V 1.5 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 V 1.5 phosphorylation. In addition, NAD + -dependent deacetylation of Na V 1.5 at K1479 by Sirtuin 1 increases Na V 1.5 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 and Results The effects of NAD + precursors on the NAD + metabolome and electrophysiology were studied using HEK293 cells expressing wild-type and mutant Na V 1.5, rat neonatal cardiomyocytes (RNCMs), and mice. NR increased I Na in HEK293 cells expressing Na V 1.5 (500 μM: 51 ± 18%, p=0.02, 5 mM: 59 ± 22%, p=0.03) and RNCMs (500 µM: 60 ± 26%, p=0.02, 5 mM: 75 ± 39%, p=0.03) while reducing I Na,L at the higher concentration (RNCMs, 5 mM: −45 ± 11%, p=0.04). NR (5 mM) decreased Na V 1.5 K1479 acetylation but increased I Na in HEK293 cells expressing a mutant form of Na V 1.5 with disruption of the acetylation site (Na V 1.5-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 V 1.5, but increased I Na in HEK293 cells expressing Na V 1.5-K1479A. Dietary supplementation with NR for 10-12 weeks decreased QTc in C57BL/6J mice (0.35% NR: −4.9 ± 2.0%, p=0.26; 1.0% NR: −9.5 ± 2.8%, p=0.01). Conclusions NAD + precursors differentially regulate Na V 1.5 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 V 1.5 deficiency and/or dysfunction.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":128956,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9632,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":499321,"name":"Jin‐Young Yoon","orcid":"0000-0002-5707-3636","position":1,"is_corresponding":false},{"id":393090,"name":"Jared M. McLendon","orcid":"0000-0002-1002-5872","position":2,"is_corresponding":false},{"id":499322,"name":"Haider Mehdi","orcid":"0000-0001-7591-8180","position":3,"is_corresponding":false},{"id":228944,"name":"Mark S. Schmidt","orcid":"0000-0003-4593-4096","position":4,"is_corresponding":false},{"id":500199,"name":"Alexander M. Greiner","orcid":null,"position":5,"is_corresponding":false},{"id":499323,"name":"Pravda Quinones","orcid":"0000-0002-4037-8804","position":6,"is_corresponding":false},{"id":499324,"name":"Gina Morgan","orcid":"0000-0003-2579-1657","position":7,"is_corresponding":false},{"id":499325,"name":"Ryan L. Boudreau","orcid":"0000-0002-9800-5349","position":8,"is_corresponding":false},{"id":443378,"name":"Kaikobad Irani","orcid":"0000-0001-9194-7387","position":9,"is_corresponding":false},{"id":201107,"name":"Charles Brenner","orcid":"0000-0002-4955-3226","position":10,"is_corresponding":false},{"id":32972,"name":"Barry London","orcid":"0000-0003-1506-3947","position":11,"is_corresponding":false},{"id":499320,"name":"Daniel S. Matasic","orcid":"0000-0001-7010-6298","position":0,"is_corresponding":true}],"reference_count":42,"raw_metadata":null,"created_at":"2026-07-18T23:15:42.522809Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}