A Mutation Causing Brugada Syndrome Identifies a Mechanism for Altered Autonomic and Oxidant Regulation of Cardiac Sodium Currents

作者：Aiba Takeshi; Farinelli Federica; Kostecki Geran; Hesketh Geoffrey G; Edwards David; Biswas Subrata; Tung Leslie; Tomaselli Gordon F^*

来源：Circulation-Cardiovascular Genetics, 2014, 7(3): 249-256.

DOI：10.1161/CIRCGENETICS.113.000480

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

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 (I-Na) 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 I-Na 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 I-Na and conduction velocity of WT but not mutant channels. Oxidant stress inhibits cardiac I-Na; WT and mutant I-Na 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 I-Na 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.

• 出版日期2014-6