Cardiac Na+ Current regulation by pyridine nucleotides

Man Liu, Shamarendra Sanyal, Ge Gao, Iman S. Gurung, Xiaodong Zhu, Georgia Gaconnet, Laurie J. Kerchner, Lijuan L. Shang, Christopher L.H. Huang, Andrew Grace, Barry London, Samuel C. Dudley

Research output: Contribution to journalArticle

71 Scopus citations

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<0.001). NADH application or cotransfection with A280V GPD1-L resulted in decreased INa (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, 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.

Original languageEnglish (US)
Pages (from-to)737-745
Number of pages9
JournalCirculation research
Volume105
Issue number8
DOIs
StatePublished - Oct 2009
Externally publishedYes

Keywords

  • Arrhythmias
  • Electrophysiology
  • Ion channels
  • Sudden death

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