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.
Highlights
This review aims to highlight this role by describing current understanding of the role of voltage sensor relaxation in the slow deactivation gating of hERG channels
Taken together with the observed role of the S4–S5 linker in coupling pore motions to stabilization of the S4 described in the previous section, these findings indicate dual regulation, i.e., at both extracellular and intracellular ends, of S4 movement that contributes to mode-shift behavior in hERG channels and their unique slow deactivation properties
In this review we have discussed current knowledge pertaining to the mechanistic determinants of hysteretic behavior in hERG channels and how this might influence deactivation gating and resurgent repolarizing current during the cardiac action potential
Summary
Recent cryogenic electron microscopy (cryo-EM) structures of the hERG channel and the related eag channel in a depolarized conformation have provided direct and highly valuable insight into understanding the gating properties of hERG channels and their role in the heart and drug discovery (Whicher and MacKinnon, 2016; Wang and MacKinnon, 2017). The S6 segment of hERG channels lacks a proline-valine-proline (PVP) motif that would narrow the pore region and which, in other channels, is suggested to orient the S6 to allow it to interact with the S4–S5 linker The lack of this structure combined with the short non-domain swapped S4–S5 linker contributes to the idea that eag family channels may have unconventional means of electromechanical coupling (Thouta et al, 2014; Lörinczi et al, 2015; Whicher and MacKinnon, 2016; Malak et al, 2017; Malak et al, 2019). Further structures of closed channel state would undoubtedly contribute to our understanding of the dynamic structure of hERG channels
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
