Mutations of the cardiac voltage-gated sodium channel (SCN5A gene encoding voltage-gated sodium channel [Na_V1.5]) cause congenital long-QT syndrome type 3 (LQT3). Most Na_V1.5 mutations associated with LQT3 promote a mode of sodium channel gating in which some channels fail to inactivate, contributing to increased late sodium current (I_NaL), which is directly responsible for delayed repolarization and prolongation of the QT interval. LQT3 patients have highest risk of arrhythmia during sleep or during periods of slow heart rate. During exercise (high heart rate), there is elevated steady-state intracellular free calcium (Ca²⁺) concentration. We hypothesized that higher levels of intracellular Ca²⁺ may lower arrhythmia risk in LQT3 subjects through effects on I_NaL.

We tested this idea by examining the effects of varying intracellular Ca²⁺ concentrations on the level of I_NaL in cells expressing a typical LQT3 mutation, delKPQ, and another SCN5A mutation, R225P. We found that elevated intracellular Ca²⁺ concentration significantly reduced I_NaL conducted by mutant channels but not wild-type channels. This attenuation of I_NaL in delKPQ expressing cells by Ca²⁺ was not affected by the CaM kinase II inhibitor KN-93 but was partially attenuated by truncating the C-terminus of the channel.

We conclude that intracellular Ca²⁺ contributes to the regulation of I_NaL conducted by Na_V1.5 mutants and propose that, during excitation–contraction coupling, elevated intracellular Ca²⁺ suppresses mutant channel I_NaL and protects cells from delayed repolarization. These findings offer a plausible explanation for the lower arrhythmia risk in LQT3 subjects during fast heart rates.