Modulation of hERG K+ Channel Deactivation by Voltage Sensor Relaxation

Resource type
Date created
2020-02-28
Authors/Contributors
Abstract
The hERG (human-ether-à-go-go-related gene) channel underlies the rapid delayed rectifier current, Ikr, in the heart, which is essential for normal cardiac electrical activity and rhythm. Slow deactivation is one of the hallmark features of the unusual gating characteristics of hERG channels, and plays a crucial role in providing a robust current that aids repolarization of the cardiac action potential. As such, there is significant interest in elucidating the underlying mechanistic determinants of slow hERG channel deactivation. Recent work has shown that the hERG channel S4 voltage sensor is stabilized following activation in a process termed relaxation. Voltage sensor relaxation results in energetic separation of the activation and deactivation pathways, producing a hysteresis, which modulates the kinetics of deactivation gating. Despite widespread observation of relaxation behaviour in other voltage-gated K+ channels, such as Shaker, Kv1.2 and Kv3.1, as well as the voltage-sensing phosphatase Ci-VSP, the relationship between stabilization of the activated voltage sensor by the open pore and voltage sensor relaxation in the control of deactivation has only recently begun to be explored. In this review, we discuss present knowledge and questions raised related to the voltage sensor relaxation mechanism in hERG channels and compare structure-function aspects of relaxation with those observed in related ion channels. We focus discussion, in particular, on the mechanism of coupling between voltage sensor relaxation and deactivation gating to highlight the insight that these studies provide into the control of hERG channel deactivation gating during their physiological functioning.
Document
Published as
Shi YP, Thouta S and Claydon TW (2020) Modulation of hERG K+ Channel Deactivation by Voltage Sensor Relaxation. Front. Pharmacol. 11:139. DOI: 10.3389/fphar.2020.00139.
Publication title
Front. Pharmacol.
Document title
Modulation of hERG K+ Channel Deactivation by Voltage Sensor Relaxation
Date
2020
Volume
11
Issue
139
Publisher DOI
10.3389/fphar.2020.00139
Copyright statement
Copyright is held by the author(s).
Scholarly level
Peer reviewed?
Yes
Language
Attachment Size
fphar-11-00139.pdf 1.37 MB