In:
Scientific Reports, Springer Science and Business Media LLC, Vol. 7, No. 1 ( 2017-03-02)
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-terminus (S6 T ) completely inhibits hERG. This shows that channel S4-S5 L is sufficient to stabilize the pore activation gate in its closed state. Conversely, covalently binding a peptide mimicking S6 T to the channel S4-S5 L prevents its inhibiting effect and renders the channel almost completely voltage-independent. This shows that the channel S4-S5 L is necessary to stabilize the activation gate in its closed state. Altogether, our results provide chemical evidence that S4-S5 L acts as a voltage-controlled ligand that binds S6 T to lock the channel in a closed state, elucidating the coupling between voltage sensors and the gate in delayed rectifier potassium channels and potentially other voltage-gated channels.
Type of Medium:
Online Resource
ISSN:
2045-2322
DOI:
10.1038/s41598-017-00155-2
Language:
English
Publisher:
Springer Science and Business Media LLC
Publication Date:
2017
detail.hit.zdb_id:
2615211-3
