The human ether-à-go-go-related gene (hERG) encodes a potassium (K + ) channel that conducts the rapid delayed rectifier current (I Kr ), which is a key component in the repolarization phase of the ventricular action potential (AP). Genetic mutations in hERG are found in patients with Long QT syndrome 2 (LQT2), a congenital disorder that is characterized by prolongation of the QT interval on an electrocardiogram and increased susceptibility to severe cardiac arrhythmias. hERG is a voltage gated channel with six transmembrane domains (S1-S6) wherein the S4 domain constitutes the voltage sensing domain (VSD) containing positively charged residues that are important in regulating voltage sensing function. We used whole-cell patch clamp to investigate the biophysical properties of hERG channels harboring clinically relevant mutations at these key sites. When transfected into HEK293 cells, the hERG S4 domain mutations shifted the half maximal activation (V 1/2 ) to both hyperpolarized and depolarized voltages. The changes in V 1/2 were accompanied by various changes in biophysical functions including hyperpolarized and depolarized shifts in steady-state inactivation, faster activation, and slower deactivation. We integrated the biophysical profiles of hERG mutants into a computational model of human ventricular cardiomyocytes to systematically delineate and quantify their impact on hERG currents and AP morphology and dynamics. For some mutants, gating defects alone were sufficient to cause hERG loss-of-function and prolong the AP. For others, altered gating did not impact AP duration unless accompanied by reduced current density, likely resulting from impaired channel trafficking. We propose that mutations at the charged residues in the S4 segment of the hERG VSD prolong the cardiac AP by producing a spectrum of effects on channel gating and trafficking.
McNair et al. (Sun,) studied this question.