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Circulation Research
0009-7330 Vol.105, 08(2009)
Cardiac Na+ Current Regulation by Pyridine Nucleotides
Liu, Man; Sanyal, Shamarendra; Gao, Ge; Gurung, Iman S.; Zhu, Xiaodong; Gaconnet, Georgia; Kerchner, Laurie J.; Shang, Lijuan L.; Huang, Christopher L.-H.; Grace, Andrew; London, Barry; Dudley, Samuel C., Jr
 Abstract:Rationale: Mutations in glycerol-3-phosphate dehydrogenase 1-like (GPD1-L) protein reduce cardiac Na+ current (INa) 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 (Nav1.5). Methods and Results: HEK293 cells stably expressing Nav1.5 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 cotransfection with A280V GPD1-L resulted in decreased INa (0.48±0.09 or 0.19±0.04 of control group, respectively; P 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, PKAI6–22. 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 Nav1.5 is regulated by pyridine nucleotides, suggesting a link between metabolism and INa. 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 Nav1.5 by altering the oxidized to reduced NAD(H) balance.
 Keyword:arrhythmias ? electrophysiology ? ion channels ? sudden death
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