Key result
Mexiletine increases sodium current density ~4-fold in mutant SCN5A channels, restoring wild-type levels.
Why the study?
Common SCN5A polymorphisms S524Y and H558R cause reduced sodium current density in the Q1077 splice variant, and whether mexiletine can rescue these expression defects was investigated.
Does mexiletine improve sodium current density and cell-surface expression in HEK-293 cells expressing SCN5A polymorphisms S524Y and H558R in the Q1077 splice variant?
Does mexiletine improve sodium current density and cell-surface expression in HEK-293 cells expressing SCN5A polymorphisms S524Y and H558R in the Q1077 splice variant?
Mexiletine rescues the expression and functional defects of SCN5A common polymorphisms S524Y and H558R in the Q1077 splice variant, suggesting a potential therapeutic mechanism for loss-of-function channelopathies.
Answers are grounded in this paper and cite their sources.
Hypothesis-generating for mexiletine rescue in SCN5A carriers; does not support clinical use without trials.
The cardiac sodium channel NaV1.5, encoded by SCN5A, generates the inward sodium current required for myocardial excitability and impulse conduction. Loss-of-function mutations of NaV1.5 have been implicated in inherited arrhythmia syndromes, including Brugada syndrome, progressive cardiac conduction disease, and congenital sick sinus syndrome. The common SCN5A polymorphism H558R has reported minor allele frequencies ranging from 9.2% to 29% across ethnic groups, whereas S524Y has been described in individuals of African ancestry with a minor allele frequency of approximately 3.3%. Two splice variants of human SCN5A, one lacking a glutamine at position 1077 (Q1077del) and one containing Q1077, exist in every human in a 2:1 mRNA transcript ratio. We engineered these two polymorphisms in both backgrounds and reported that when S524Y and H558R were expressed in the Q1077del variant, current densities were normal. In the Q1077 variant, however, the current densities showed a dramatic reduction compared to those in the Q1077del variant or WT-Q1077. We previously reported that incubation with the antiarrhythmic drug mexiletine “rescued” expression deficiencies in the Brugada syndrome. Cells expressing S524Y/Q1077 and H558R/Q1077 were incubated for 48 h with or without mexiletine (500 μM), followed by drug washout before electrophysiological assessment. Mexiletine significantly increased current density for both S524Y/Q1077 and H558R/Q1077 compared with untreated cells, restoring current density to levels comparable to WT-Q1077. Flow cytometry using a FLAG-tagged channel demonstrated that mexiletine-mediated rescue was associated with increased cell-surface expression. The magnitude of the expression defects caused by H558R and S524Y in the Q1077 splice background is similar to that observed with arrhythmia-associated SCN5A mutations, and we show for the first time that the defects for both polymorphisms can be rescued with mexiletine. Although it is unknown whether they result in heightened arrhythmia susceptibility in patients homozygous for the minor allele, our result may have implications for therapy for mutations with loss-of-function phenotypes modified by these common polymorphisms.
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Hu et al. (2026) studied SCN5A loss-of-function mutations (in vitro model). Mexiletine vs. Untreated cells was evaluated on Na+ current (INa) density for S524Y/Q1077 (pA/pF) (p=<0.005). Mexiletine significantly increased sodium current density for both S524Y/Q1077 and H558R/Q1077 channels compared with untreated cells, restoring current density to levels comparable to wild-type.
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