Effects of Mexiletine on a Race-specific Mutation in Nav1.5 Associated With Long QT Syndrome

The voltage-gated sodium channel Na(v)1.5 plays an essential role in the generation and propagation of action potential in cardiomyocytes. Mutations in Na(v)1.5 have been associated with LQT syndrome, Brugada syndrome, and sudden arrhythmia death syndrome. Genetic studies showed that Na(v)1.5 mutations vary across race-ethnic groups. Here we investigated an Asian-specific mutation Na(v)1.5-P1090L associated with LQT syndrome. We found that Na(v)1.5-P1090L mutation perturbed the sodium channel function. It altered the gating process of the channel and exhibited an enhanced window current. Treatment with mexiletine reversed the depolarization shift of the steady-state inactivation produced by P1090L. Mexiletine also modified the recovery from steady-state inactivation and the development of inactivation of P1090L. It rescued the dysfunctional inactivation of P1090L and reduced the P1090L channel's availability.

Automated summary

The voltage-gated sodium channel Na(v)1.5 is crucial for generating and propagating action potentials in cardiomyocytes. Mutations in Na(v)1.5 have been linked to various heart rhythm disorders. This study focused on an Asian-specific mutation called Na(v)1.5-P1090L, which was associated with long QT syndrome. The mutation disrupted the function of the sodium channel and could be reversed by treatment with mexiletine.