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http://purl.uniprot.org/citations/19745168http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/19745168http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/19745168http://www.w3.org/2000/01/rdf-schema#comment"

Rationale

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).

Methods and 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."xsd:string
http://purl.uniprot.org/citations/19745168http://purl.org/dc/terms/identifier"doi:10.1161/circresaha.109.197277"xsd:string
http://purl.uniprot.org/citations/19745168http://purl.org/dc/terms/identifier"doi:10.1161/circresaha.109.197277"xsd:string
http://purl.uniprot.org/citations/19745168http://purl.uniprot.org/core/author"Liu M."xsd:string
http://purl.uniprot.org/citations/19745168http://purl.uniprot.org/core/author"Liu M."xsd:string
http://purl.uniprot.org/citations/19745168http://purl.uniprot.org/core/author"Zhu X."xsd:string
http://purl.uniprot.org/citations/19745168http://purl.uniprot.org/core/author"Zhu X."xsd:string
http://purl.uniprot.org/citations/19745168http://purl.uniprot.org/core/author"Gao G."xsd:string
http://purl.uniprot.org/citations/19745168http://purl.uniprot.org/core/author"Gao G."xsd:string
http://purl.uniprot.org/citations/19745168http://purl.uniprot.org/core/author"Sanyal S."xsd:string
http://purl.uniprot.org/citations/19745168http://purl.uniprot.org/core/author"Sanyal S."xsd:string
http://purl.uniprot.org/citations/19745168http://purl.uniprot.org/core/author"Grace A."xsd:string
http://purl.uniprot.org/citations/19745168http://purl.uniprot.org/core/author"Grace A."xsd:string
http://purl.uniprot.org/citations/19745168http://purl.uniprot.org/core/author"London B."xsd:string
http://purl.uniprot.org/citations/19745168http://purl.uniprot.org/core/author"London B."xsd:string
http://purl.uniprot.org/citations/19745168http://purl.uniprot.org/core/author"Huang C.L."xsd:string
http://purl.uniprot.org/citations/19745168http://purl.uniprot.org/core/author"Huang C.L."xsd:string
http://purl.uniprot.org/citations/19745168http://purl.uniprot.org/core/author"Dudley S.C. Jr."xsd:string
http://purl.uniprot.org/citations/19745168http://purl.uniprot.org/core/author"Dudley S.C. Jr."xsd:string
http://purl.uniprot.org/citations/19745168http://purl.uniprot.org/core/author"Gaconnet G."xsd:string
http://purl.uniprot.org/citations/19745168http://purl.uniprot.org/core/author"Gaconnet G."xsd:string
http://purl.uniprot.org/citations/19745168http://purl.uniprot.org/core/author"Gurung I.S."xsd:string
http://purl.uniprot.org/citations/19745168http://purl.uniprot.org/core/author"Gurung I.S."xsd:string
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