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Circ Cardiovasc Genet. 2014 Jun;7(3):249-56. doi: 10.1161/CIRCGENETICS.113.000480. Epub 2014 May 2.

A mutation causing Brugada syndrome identifies a mechanism for altered autonomic and oxidant regulation of cardiac sodium currents.

Author information

1
From the Division of Cardiology, Department of Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (T.A., F.F., D.E., S.B., G.F.T.); and Department of Biomedical Engineering (G.K., L.T.) and Department of Biological Chemistry (G.G.H.), Johns Hopkins University, Baltimore, MD.
2
From the Division of Cardiology, Department of Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (T.A., F.F., D.E., S.B., G.F.T.); and Department of Biomedical Engineering (G.K., L.T.) and Department of Biological Chemistry (G.G.H.), Johns Hopkins University, Baltimore, MD. gtomasel@jhmi.edu.

Abstract

BACKGROUND:

The mechanisms of the electrocardiographic changes and arrhythmias in Brugada syndrome (BrS) remain controversial. Mutations in the sodium channel gene, SCN5A, and regulatory proteins that reduce or eliminate sodium current (INa) have been linked to BrS. We studied the properties of a BrS-associated SCN5A mutation in a protein kinase A (PKA) consensus phosphorylation site, R526H.

METHODS AND RESULTS:

In vitro PKA phosphorylation was detected in the I-II linker peptide of wild-type (WT) channels but not R526H or S528A (phosphorylation site) mutants. Cell surface expression of R526H and S528A channels was reduced compared with WT. Whole-cell INa through all channel variants revealed no significant differences in the steady-state activation, inactivation, and recovery from inactivation. Peak current densities of the mutants were significantly reduced compared with WT. Infection of 2D cultures of neonatal rat ventricular myocytes with WT and mutant channels increased conduction velocity compared with noninfected cells. PKA stimulation significantly increased peak INa and conduction velocity of WT but not mutant channels. Oxidant stress inhibits cardiac INa; WT and mutant INa decreases with the intracellular application of reduced nicotinamide adenine dinucleotide (NADH), an effect that is reversed by PKA stimulation in WT but not in R526H or S528A channels.

CONCLUSIONS:

We identified a family with BrS and an SCN5A mutation in a PKA consensus phosphorylation site. The BrS mutation R526H is associated with a reduction in the basal level of INa and a failure of PKA stimulation to augment the current that may contribute to the predisposition to arrhythmias in patients with BrS, independent of the precipitants.

KEYWORDS:

death, sudden, cardiac; ion channel; mutation; reactive oxygen species

PMID:
24795344
PMCID:
PMC4114079
DOI:
10.1161/CIRCGENETICS.113.000480
[Indexed for MEDLINE]
Free PMC Article
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