The S4-S5 linker acts as a signal integrator for HERG K+ channel activation and deactivation gating.

Human ether-à-go-go-related gene (hERG) K(+) channels have unusual gating kinetics. Characterised by slow activation/deactivation but rapid inactivation/recovery from inactivation, the unique gating kinetics underlie the central role hERG channels play in cardiac repolarisation. The slow activation...

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Autores principales:	Chai Ann Ng, Matthew D Perry, Peter S Tan, Adam P Hill, Philip W Kuchel, Jamie I Vandenberg
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/c738808abc224046af0e7d81d27c1e04
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spelling	oai:doaj.org-article:c738808abc224046af0e7d81d27c1e042021-11-18T07:27:58ZThe S4-S5 linker acts as a signal integrator for HERG K+ channel activation and deactivation gating.1932-620310.1371/journal.pone.0031640https://doaj.org/article/c738808abc224046af0e7d81d27c1e042012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22359612/?tool=EBIhttps://doaj.org/toc/1932-6203Human ether-à-go-go-related gene (hERG) K(+) channels have unusual gating kinetics. Characterised by slow activation/deactivation but rapid inactivation/recovery from inactivation, the unique gating kinetics underlie the central role hERG channels play in cardiac repolarisation. The slow activation and deactivation kinetics are regulated in part by the S4-S5 linker, which couples movement of the voltage sensor domain to opening of the activation gate at the distal end of the inner helix of the pore domain. It has also been suggested that cytosolic domains may interact with the S4-S5 linker to regulate activation and deactivation kinetics. Here, we show that the solution structure of a peptide corresponding to the S4-S5 linker of hERG contains an amphipathic helix. The effects of mutations at the majority of residues in the S4-S5 linker of hERG were consistent with the previously identified role in coupling voltage sensor movement to the activation gate. However, mutations to Ser543, Tyr545, Gly546 and Ala548 had more complex phenotypes indicating that these residues are involved in additional interactions. We propose a model in which the S4-S5 linker, in addition to coupling VSD movement to the activation gate, also contributes to interactions that stabilise the closed state and a separate set of interactions that stabilise the open state. The S4-S5 linker therefore acts as a signal integrator and plays a crucial role in the slow deactivation kinetics of the channel.Chai Ann NgMatthew D PerryPeter S TanAdam P HillPhilip W KuchelJamie I VandenbergPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 2, p e31640 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Chai Ann Ng Matthew D Perry Peter S Tan Adam P Hill Philip W Kuchel Jamie I Vandenberg The S4-S5 linker acts as a signal integrator for HERG K+ channel activation and deactivation gating.
description	Human ether-à-go-go-related gene (hERG) K(+) channels have unusual gating kinetics. Characterised by slow activation/deactivation but rapid inactivation/recovery from inactivation, the unique gating kinetics underlie the central role hERG channels play in cardiac repolarisation. The slow activation and deactivation kinetics are regulated in part by the S4-S5 linker, which couples movement of the voltage sensor domain to opening of the activation gate at the distal end of the inner helix of the pore domain. It has also been suggested that cytosolic domains may interact with the S4-S5 linker to regulate activation and deactivation kinetics. Here, we show that the solution structure of a peptide corresponding to the S4-S5 linker of hERG contains an amphipathic helix. The effects of mutations at the majority of residues in the S4-S5 linker of hERG were consistent with the previously identified role in coupling voltage sensor movement to the activation gate. However, mutations to Ser543, Tyr545, Gly546 and Ala548 had more complex phenotypes indicating that these residues are involved in additional interactions. We propose a model in which the S4-S5 linker, in addition to coupling VSD movement to the activation gate, also contributes to interactions that stabilise the closed state and a separate set of interactions that stabilise the open state. The S4-S5 linker therefore acts as a signal integrator and plays a crucial role in the slow deactivation kinetics of the channel.
format	article
author	Chai Ann Ng Matthew D Perry Peter S Tan Adam P Hill Philip W Kuchel Jamie I Vandenberg
author_facet	Chai Ann Ng Matthew D Perry Peter S Tan Adam P Hill Philip W Kuchel Jamie I Vandenberg
author_sort	Chai Ann Ng
title	The S4-S5 linker acts as a signal integrator for HERG K+ channel activation and deactivation gating.
title_short	The S4-S5 linker acts as a signal integrator for HERG K+ channel activation and deactivation gating.
title_full	The S4-S5 linker acts as a signal integrator for HERG K+ channel activation and deactivation gating.
title_fullStr	The S4-S5 linker acts as a signal integrator for HERG K+ channel activation and deactivation gating.
title_full_unstemmed	The S4-S5 linker acts as a signal integrator for HERG K+ channel activation and deactivation gating.
title_sort	s4-s5 linker acts as a signal integrator for herg k+ channel activation and deactivation gating.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/c738808abc224046af0e7d81d27c1e04
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The S4-S5 linker acts as a signal integrator for HERG K+ channel activation and deactivation gating.

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