Abstract
K+ channels control transmembrane action potentials by gating open or closed in response to external stimuli. Inactivation gating, involving a conformational change at the K+ selectivity filter, has recently been recognized as a major K+ channel regulatory mechanism. In the K+ channel hERG, inactivation controls the length of the human cardiac action potential. Mutations impairing hERG inactivation cause life-threatening cardiac arrhythmia, which also occur as undesired side effects of drugs. In this paper, we report atomistic molecular dynamics simulations, complemented by mutational and electrophysiological studies, which suggest that the selectivity filter adopts a collapsed conformation in the inactivated state of hERG. The selectivity filter is gated by an intricate hydrogen bond network around residues S620 and N629. Mutations of this hydrogen bond network are shown to cause inactivation deficiency in electrophysiological measurements. In addition, drug-related conformational changes around the central cavity and pore helix provide a functional mechanism for newly discovered hERG activators.
Highlights
Regulated current through K+ channels plays an essential role in cellular ionic homeostasis and intercellular signaling [1]
[28], we carried out a computational interaction scan, in which the distance between the side chains of S620 and N629 was systematically varied in intervals of 1 A (Fig. 1A)
Inactivation of hERG is of crucial physiological and medical importance, as it is instrumental in controlling the duration of the cardiac action potential
Summary
Regulated current through K+ channels plays an essential role in cellular ionic homeostasis and intercellular signaling [1]. Activation gating – a large-scale reconfiguration of the pore-forming transmembrane helices – had long been viewed as the main regulatory switch of K+ channels, C-type inactivation and the coupling between activation and inactivation have recently been recognized as general control mechanisms of K+ channel gating [2,3,4,5,6]. C-type inactivation plays a important role in the K+ channel hERG (human ether-a-go-go related gene potassium channel, Kv11.1). HERG is a channel protein predominantly expressed in human cardiac myocyte membranes [10,11]. It forms a pore at the interface of four subunits each containing six transmembrane (TM) helices and the pore helix. As the repolarization phase of the human cardiac action potential is governed by flux through hERG, its kinetics determine the length of the action potential and, thereby, strongly contribute to normal function of the heart [10,13]
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