Loss-of-function mutations in Nav1.5 cause sodium channelopathies, including Brugada syndrome, dilated cardiomyopathy, and sick sinus syndrome; however, no effective therapy exists. MOG1 increases plasma membrane (PM) expression of Nav1.5 and sodium current (INa) density, thus we hypothesize that MOG1 can serve as a therapeutic target for sodium channelopathies.Methods and Results—
Knockdown of MOG1 expression using small interfering RNAs reduced Nav1.5 PM expression, decreased INa densities by 2-fold in HEK/Nav1.5 cells and nearly abolished INa in mouse cardiomyocytes. MOG1 did not affect Nav1.5 PM turnover. MOG1 small interfering RNAs caused retention of Nav1.5 in endoplasmic reticulum, disrupted the distribution of Nav1.5 into caveolin-3–enriched microdomains, and led to redistribution of Nav1.5 to noncaveolin-rich domains. MOG1 fully rescued the reduced PM expression and INa densities by Nav1.5 trafficking–defective mutation D1275N associated with sick sinus syndrome/dilated cardiomyopathy/atrial arrhythmias. For Brugada syndrome mutation G1743R, MOG1 restored the impaired PM expression of the mutant protein and restored INa in a heterozygous state (mixture of wild type and mutant Nav1.5) to a full level of a homozygous wild-type state.Conclusions—
Use of MOG1 to enhance Nav1.5 trafficking to PM may be a potential personalized therapeutic approach for some patients with Brugada syndrome, dilated cardiomyopathy, and sick sinus syndrome in the future.