Background—
Loss-of-function mutations in Na
v
1.5 cause sodium channelopathies, including Brugada syndrome, dilated cardiomyopathy, and sick sinus syndrome; however, no effective therapy exists. MOG1 increases plasma membrane (PM) expression of Na
v
1.5 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 Na
v
1.5 PM expression, decreased
INa
densities by 2-fold in HEK/Na
v
1.5 cells and nearly abolished
INa
in mouse cardiomyocytes. MOG1 did not affect Na
v
1.5 PM turnover.
MOG
1 small interfering RNAs caused retention of Na
v
1.5 in endoplasmic reticulum, disrupted the distribution of Na
v
1.5 into caveolin-3–enriched microdomains, and led to redistribution of Na
v
1.5 to noncaveolin-rich domains. MOG1 fully rescued the reduced PM expression and
INa
densities by Na
v
1.5 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 Na
v
1.5) to a full level of a homozygous wild-type state.
Conclusions—
Use of MOG1 to enhance Na
v
1.5 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.
