title: Cardiac Na+ current regulation by pyridine nucleotides.
abstract: BACKGROUND
  Mutations in glycerol-3-phosphate dehydrogenase 1-like (GPD1-L) protein reduce cardiac Na+ current (I(Na)) and cause Brugada Syndrome (BrS). GPD1-L has >80% amino acid homology with glycerol-3-phosphate dehydrogenase, which is involved in NAD-dependent energy metabolism.
  
  
  OBJECTIVE
  Therefore, we tested whether NAD(H) could regulate human cardiac sodium channels (Na(v)1.5).
  
  
  RESULTS
  HEK293 cells stably expressing Na(v)1.5 and rat neonatal cardiomyocytes were used. The influence of NADH/NAD+ on arrhythmic risk was evaluated in wild-type or SCN5A(+/-) mouse heart. A280V GPD1-L caused a 2.48+/-0.17-fold increase in intracellular NADH level (P<0.001). NADH application or cotransfection with A280V GPD1-L resulted in decreased I(Na) (0.48+/-0.09 or 0.19+/-0.04 of control group, respectively; P<0.01), which was reversed by NAD+, chelerythrine, or superoxide dismutase. NAD+ antagonism of the Na+ channel downregulation by A280V GPD1-L or NADH was prevented by a protein kinase (PK)A inhibitor, PKAI(6-22). The effects of NADH and NAD+ were mimicked by a phorbol ester and forskolin, respectively. Increasing intracellular NADH was associated with an increased risk of ventricular tachycardia in wild-type mouse hearts. Extracellular application of NAD+ to SCN5A(+/-) mouse hearts ameliorated the risk of ventricular tachycardia.
  
  
  CONCLUSIONS
  Our results show that Na(v)1.5 is regulated by pyridine nucleotides, suggesting a link between metabolism and I(Na). This effect required protein kinase C activation and was mediated by oxidative stress. NAD+ could prevent this effect by activating PKA. Mutations of GPD1-L may downregulate Na(v)1.5 by altering the oxidized to reduced NAD(H) balance.
authors.affiliation: Division in Cardiology, University of Illinois at Chicago and the Jesse Brown Veteran Affairs Medical Center, Chicago, IL 60612, USA.
authors.forename: Man
authors.initials: M
authors.lastname: Liu
authors.forename: Shamarendra
authors.initials: S
authors.lastname: Sanyal
authors.forename: Ge
authors.initials: G
authors.lastname: Gao
authors.forename: Iman S
authors.initials: IS
authors.lastname: Gurung
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zhu
authors.forename: Georgia
authors.initials: G
authors.lastname: Gaconnet
authors.forename: Laurie J
authors.initials: LJ
authors.lastname: Kerchner
authors.forename: Lijuan L
authors.initials: LL
authors.lastname: Shang
authors.forename: Christopher L-H
authors.initials: CL
authors.lastname: Huang
authors.forename: Andrew
authors.initials: A
authors.lastname: Grace
authors.forename: Barry
authors.initials: B
authors.lastname: London
authors.forename: Samuel C
authors.initials: SC
authors.lastname: Dudley
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D053119:Benzophenanthridines / Q000494:pharmacology; D053840:Brugada Syndrome / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005993:Glycerolphosphate Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009206:Myocardium / Q000378:metabolism; D009243:NAD / Q000235:genetics / Q000378:metabolism*; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010084:Oxidation-Reduction; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051381:Rats; D012964:Sodium / Q000378:metabolism*; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D017180:Tachycardia, Ventricular / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D053119:Benzophenanthridines; D004791:Enzyme Inhibitors; D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; C568321:Scn5a protein, mouse; C568322:Scn5a protein, rat; D015222:Sodium Channels; D009243:NAD; D012964:Sodium; C016299:chelerythrine; C525035:GPD1L protein, human; D005993:Glycerolphosphate Dehydrogenase; D013482:Superoxide Dismutase; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C