NS1643 enhances the activity of T1019PfsX38 and Q1070X hERG channels associated with long QT syndrome type 2
TL;DR
It is concluded that the functions of T1019PfsX38- and Q1070X-hERG channels can be augmented by hERG potentiators if NMD is incomplete, which may facilitate the development of a mechanism-based rescue approach.
Abstract
Type 2 long QT syndrome (LQT2) increases the risk of cardiac arrest and sudden death due to reduced rapid delayed rectifier potassium currents (IKr) in the heart. Caused by loss-of-function genetic variants in the hERG K+ channel, LQT2 might benefit from variant-targeted therapy approaches. T1019PfsX38 and Q1070X are LQT2-causing variants reported in Oman and Saudi Arabia. Although nonsense-mediated mRNA decay (NMD) has been proposed to contribute to reduced expression of these truncating variants, it remains unclear whether residual mutant hERG channel function can be pharmacologically enhanced. We used the patch-clamp technique and examined the effects of the hERG potentiator NS1643 on wild-type-, T1019PfsX38- and Q1070X-hERG channels expressed in HEK293 cells. We started by assessing the response of these variants under the influence of a ventricular action potential clamp protocol, then used additional protocols to elucidate the drug’s mechanism of action. NS1643 [10 µM] enhanced the repolarization currents in wild-type-, T1019PfsX38- and Q1070X-expressing cells. Its effect was associated with accelerated activation rates and a negative shift in the voltage dependence of activation. In addition, NS1643 suppressed fast deactivation transitions. We conclude that the functions of T1019PfsX38- and Q1070X-hERG channels can be augmented by hERG potentiators if NMD is incomplete, which may facilitate the development of a mechanism-based rescue approach.