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PMID: 19745168 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Cardiac Na+ current regulation by pyridine nucleotides.

Circulation research ·Vol. 105 ·No. 8 ·2009-10-09 ·Pages 737-45

Liu M, Sanyal S, Gao G, Gurung IS, Zhu X, Gaconnet G, Kerchner LJ, Shang LL, Huang CL, Grace A, London B, Dudley SC

Abstract

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. Therefore, we tested whether NAD(H) could regulate human cardiac sodium channels (Na(v)1.5). 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. 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.

MeSH Terms
Animals Antineoplastic Agents/pharmacology Benzophenanthridines/pharmacology Brugada Syndrome/genetics,metabolism Cell Line Cyclic AMP-Dependent Protein Kinases/antagonists & inhibitors,genetics,metabolism Down-Regulation/drug effects,genetics Enzyme Inhibitors/pharmacology Glycerolphosphate Dehydrogenase/genetics,metabolism Humans Mice Muscle Proteins/genetics,metabolism Mutation Myocardium/metabolism NAD/genetics,metabolism NAV1.5 Voltage-Gated Sodium Channel Oxidation-Reduction Protein Kinase C/antagonists & inhibitors,genetics,metabolism Rats Sodium/metabolism Sodium Channels/genetics,metabolism Superoxide Dismutase/genetics,metabolism Tachycardia, Ventricular/genetics,metabolism
Chemicals
Antineoplastic Agents Benzophenanthridines Enzyme Inhibitors Muscle Proteins NAV1.5 Voltage-Gated Sodium Channel SCN5A protein, human Scn5a protein, mouse Scn5a protein, rat Sodium Channels NAD Sodium chelerythrine GPD1L protein, human Glycerolphosphate Dehydrogenase Superoxide Dismutase Cyclic AMP-Dependent Protein Kinases Protein Kinase C
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Liu Man
Division in Cardiology, University of Illinois at Chicago and the Jesse Brown Veteran Affairs Medical Center, Chicago, IL 60612, USA.
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
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Article Info
Journal
Circulation research
Abbr.
Circ Res
ISSN
1524-4571
DOI
10.1161/CIRCRESAHA.109.197277
Published
2009-10-09
Epub
2009-00-10
Pages
737-45
Language
English
Region
United States
NLM ID
0047103
PMCID
PMC2773656
Subset
IM
Grants
NHLBI NIH HHS · R01 HL106592 · United States
NHLBI NIH HHS · R01 HL085520 · United States
NHLBI NIH HHS · R01 HL085558 · United States
NHLBI NIH HHS · R01 HL106592-01A1 · United States
NHLBI NIH HHS · R01 HL073753 · United States
Wellcome Trust · 077156/Z/05/Z · United Kingdom
Wellcome Trust · United Kingdom
NHLBI NIH HHS · R01 HL062300 · United States
NHLBI NIH HHS · R01 HL085558-03 · United States
Corrections
CommentIn
PMID: 19815826
External Links
PubMed source DOI: 10.1161/CIRCRESAHA.109.197277 PMC Full Text View journal details
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