Intracellular Calcium Attenuates Persistent Current Conducted by Mutant Human Cardiac Sodium Channels in Long-QT Syndrome

Abstract

Mutation in the cardiac voltage-gated sodium channel NaV1.5 can cause congenital long-QT syndrome type 3 (LQT3). Most NaV1.5 mutations associated with LQT3 promote a mode of sodium channel gating in which some channels fail to inactivate, contributing to sustained or persistent sodium current (INa,P), 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 an increase in the steady-state intracellular free calcium (Ca) concentration. We hypothesized that higher levels of intracellular Ca may act in some way to lower arrhythmia risk in LQT3 subjects. We tested this idea by examining the effects of varying intracellular Ca concentrations on the level of INa,P in cells expressing a typical LQT3 mutation, delKPQ. We found that elevated intracellular Ca concentration significantly reduced INa,P conducted by delKPQ channels but not wild-type channels. INa,P measured 200-ms after the peak transient current (expressed as % of peak current) for mutant channels was 2.6±0.4% in low Ca and 0.6±0.1% in high Ca (p<0.001). This attenuation of INa,P in delKPQ expressing cells by Ca remained in the presence of KN-93 indicating it was not due to CaM kinase II activation (2.2±0.2% in low Ca and 0.9±0.3% in high Ca; p<0.001). We conclude that intracellular Ca contributes to the regulation of INa,P conducted by a LQT3 mutant and propose that, during excitation-contraction coupling, the increase of intracellular free Ca may contribute to suppression of mutant channel current and protect cells from delayed repolarization. These findings help explain the increased arrhythmia risk in LQT3 during slow heart rate.