Modulation of hERG K+ Channel Deactivation by Voltage Sensor Relaxation

Abstract

The hERG (human-ether-à-go-go-related gene) channel underlies the rapid delayed rectifier current, I kr , 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.

Hysteretic Behavior in Voltage-Gated Channels

“…This suggests that VSD relaxation is an intrinsically voltage-independent process. VSD relaxation is not unique to Ci-VSP or Shaker-it can be observed in other S4-VSD proteins such as Hyperpolarizationactivated Cyclic Nucleotide-gated (HCN) channels (Mannikko et al, 2005;Elinder et al, 2006;Bruening-Wright and Larsson, 2007) and the human Ether-à-go-go-Related Gene channel (Pennefather et al, 1998;Piper et al, 2003;Thouta et al, 2017;Shi et al, 2019;Shi et al, 2020). In these cases, VSD relaxation has been proposed to play an important role in the remarkable hysteretic behavior observed in these proteins.…”

Gating and regulation of KCNH (ERG, EAG, and ELK) channels by intracellular domains

“…A defining characteristic of ELK channels is a voltage-dependent potentiation (VDP), in which longer depolarizing pulses and PI (4,5)P2 shifts the conductance-voltage relationship to more hyperpolarized potentials and slows down deactivation, consistent with a slow transition to a mode that favors channel opening [44]. hERG channels also exhibit VDP [45][46][47]. ELK channels are distributed in the CNS [41,43], including cortex and hippocampus [48].…”

Potential therapeutic drugs for COVID-19 risk prolonging QT interval targeting hERG channel

“…The hERG channel act as a tetramer and four hERG subunits are arranged in a ring-shaped manner rather linearly arranged on the membrane (Vandenberg et al 2012). Each subunit has six transmembrane fragments (S1 -S6), the N-terminal Per-Arnt-Sim (PAS) domain, and the C-terminal cyclic nucleotide-binding domain (cNBD) (Barros et al 2020, Shi et al 2020, Warmke and Ganetzky 1994. S1-S4 functions as a voltagesensing domain (VSD) and S4 provides the most important component of transmembrane voltage sensing with several positively charged residues (Barros et al 2012).…”

“…Two other transmembrane helices S5-S6 coupling with the intermediate pore loops of the four subunits constitutes the ion permeation pore-gate domain (PD) consisting of the permeation pathway, the potassium selectivity filter, and the channel gate (Figure4b) (Barros et al2020, Wang et al 2011. Importantly, N-terminal and C-terminal are respectively involved in the inactivation of the hERG channel (N-type inactivation and C-type inactivation)( Barros et al 2012, Shi et al 2020 and are also the binding sites of Hsp(Iwaiet al 2013). Therefore, an interaction between hERG blocking drugs and Hsp may involve a change of gating kinetics.…”

“…Similar to other voltage-gated potassium channels, the hERG channel has three different conformational states, namely closed, open, and inactivated, respectively (Shi et al 2020, Vandenberg et al 2017, Vandenberg et al 2012. However, hERG has its unique gating kinetics with slow activation and deactivation, but faster inactivation and recovery from inactivation, and these state changes depend on voltage changes (Shi et al 2020, Vandenberg et al 2017, leading to the inward rectifying characteristic (Smithet al 1996, Spector et al 1996. The altering rate of inactivation and deactivation reflects the potential potency of drug block.…”