Why the study?
Familial mutations impacting repolarization K+ currents conducted by the hERG1 channel are significant determinants of arrhythmogenicity.
The study elucidates the molecular mechanism by which the N629D mutation in the hERG1 channel impairs selectivity and inactivation, contributing to arrhythmogenicity.
Advances molecular view of hERG1-linked arrhythmogenicity in models; leaves open therapeutic translation pending human validation.
Significance The familial mutations impacting repolarization K + currents conducted by the hERG1 channel are significant determinants of arrhythmogenicity. Here, we show how the arrhythmogenic gain-of-function mutation (N629D) in the pore domain impairs channel selectivity and inactivation by shifting complex conformational equilibria between the conductive and nonconductive states of the selectivity filter and by impacting filter modalities. This study highlights notable differences in the permeation and inactivation dynamics in a human channel that displays a nonconventional selectivity filter.
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Miranda et al. (2020) studied this question.
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