2017
DOI: 10.1016/s1878-6480(17)30501-3
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hERG S4-S5 linker acts as a voltage-dependent ligand that binds to the activation gate and locks it in a closed state

Abstract: Delayed-rectifier potassium channels (hERG and KCNQ1) play a major role in cardiac repolarization. These channels are formed by a tetrameric pore (S5-S6) surrounded by four voltage sensor domains (S1-S4). Coupling between voltage sensor domains and the pore activation gate is critical for channel voltage-dependence. However, molecular mechanisms remain elusive. Herein, we demonstrate that covalently binding, through a disulfide bridge, a peptide mimicking the S4-S5 linker (S4-S5 L ) to the channel S6 C-terminu… Show more

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Cited by 3 publications
(12 citation statements)
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“…When the membrane is depolarized, S4 pulls S4-S5 L out of its binding pocket, leading to channel opening. This is consistent with the observation that specific S4-S5 L -mimicking peptides inhibit hK V 7.1 and hK V 11.1 channels, by replacing the endogenous segment in the binding pocket 25,26 . This mechanism was recently extended to hK V 10.2 channels 29 .…”
supporting
confidence: 91%
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“…When the membrane is depolarized, S4 pulls S4-S5 L out of its binding pocket, leading to channel opening. This is consistent with the observation that specific S4-S5 L -mimicking peptides inhibit hK V 7.1 and hK V 11.1 channels, by replacing the endogenous segment in the binding pocket 25,26 . This mechanism was recently extended to hK V 10.2 channels 29 .…”
supporting
confidence: 91%
“…We identified one activating S4-S5 L peptide in Na V Sp1 and four in hNa V 1.4, suggesting that Na V channels follow a ligand/ receptor model of voltage-dependent gating (Fig. 11c): when the membrane is depolarized, endogenous S4-S5 L stabilizes the open state of Na V channels, as indicated by the Na V Ms structure captured in the open state 8,16,17 . This contrasts with what is happening with K V channels: when the membrane is polarized, endogenous S4-S5 L stabilizes the closed state of K V channels, as suggested by several studies 25,26,29 .…”
Section: Discussionmentioning
confidence: 74%
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