Abstract
The elusive activation/deactivation mechanism of hERG is investigated, a voltage-gated potassium channel involved in severe inherited and drug-induced cardiac channelopathies, including the Long QT Syndrome. Firstly, the available structural data are integrated by providing a homology model for the closed state of the channel. Secondly, molecular dynamics combined with a network analysis revealed two distinct pathways coupling the voltage sensor domain with the pore domain. Interestingly, some LQTS-related mutations known to impair the activation/deactivation mechanism are distributed along the identified pathways, which thus suggests a microscopic interpretation of their role. Split channels simulations clarify a surprising feature of this channel, which is still able to gate when a cut is introduced between the voltage sensor domain and the neighboring helix S5. In summary, the presented results suggest possible activation/deactivation mechanisms of non-domain-swapped potassium channels that may aid in biomedical applications.
Highlights
The elusive activation/deactivation mechanism of human ether-à-go-go-related gene K+ channel (hERG) is investigated, a voltage-gated potassium channel involved in severe inherited and drug-induced cardiac channelopathies, including the Long QT Syndrome
The present study aims at filling these gaps, providing a molecular-level understanding of the activation/deactivation mechanism(s) of hERG channel by molecular dynamics simulations
In this work, we have used molecular dynamics simulations combined with a network theoretical approach to reveal possible, hereby unknown mechanisms of hERG activation/deactivation
Summary
The elusive activation/deactivation mechanism of hERG is investigated, a voltage-gated potassium channel involved in severe inherited and drug-induced cardiac channelopathies, including the Long QT Syndrome. Pathological mutations of hERG, as well as promiscuous interactions with a wide range of chemicals[3,4], can lead to premature or delayed repolarization of the cardiac membrane resulting in severe channelopathies referred to as short and long QT syndromes (SQTS and LQTS), respectively. Notwithstanding its biomedical importance, little is known on hERG mechanisms of activation and deactivation[5], probably due to the fact that structural information of the channel is still incomplete, including the closed state. The disease can be induced by the unspecific interaction of hERG with a wide range of drugs including anti-arrhythmics, antibiotics, and antihistamines[4,6,7] The severity of these conditions is such that regulatory agencies prescribe the testing of all new drugs for hERG block. Helix S4, which carries five positively charged residues, senses the voltage change and moves up or down across the membrane transmitting via a yet elusive pathway the motion to the PD that, in turn, closes or opens the channel to ion passage
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