Selectivity filter modalities and rapid inactivation of the hERG1 channel

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.