Redox regulation of KV7 channels through EF3 hand of calmodulin

Neuronal KV7 channels, important regulators of cell excitability, are among the most sensitive proteins to reactive oxygen species. The S2S3 linker of the voltage sensor was reported as a site-mediating redox modulation of the channels. Recent structural insights reveal potential interactions betwee...

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Autores: Nuñez Viadero, Eider, Jones, Frederick, Muguruza Montero, Arantza, Urrutia Iñiguez, Janire, Aguado Martínez, Alejandra, Malo de la Fuente, Covadonga, Bernardo Seisdedos, Ganeko, Domene, Carmen, Millet Aguilar-Galindo, Oscar, Gamper, Nikita, Villarroel Muñoz, Álvaro
Tipo de recurso: artículo
Fecha de publicación:2023
País:España
Institución:Universidad del País Vasco
Repositorio:Addi. Archivo Digital para la Docencia y la Investigación
OAI Identifier:oai:addi.ehu.eus:10810/60885
Acceso en línea:http://hdl.handle.net/10810/60885
Access Level:acceso abierto
Palabra clave:KCNQ
calmodulin
redox
calcium
EF-hand
signal transduction
E
coli
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spelling Redox regulation of KV7 channels through EF3 hand of calmodulinNuñez Viadero, EiderJones, FrederickMuguruza Montero, ArantzaUrrutia Iñiguez, JanireAguado Martínez, AlejandraMalo de la Fuente, CovadongaBernardo Seisdedos, GanekoDomene, CarmenMillet Aguilar-Galindo, OscarGamper, NikitaVillarroel Muñoz, ÁlvaroKCNQcalmodulinredoxcalciumEF-handsignal transductionEcoliNeuronal KV7 channels, important regulators of cell excitability, are among the most sensitive proteins to reactive oxygen species. The S2S3 linker of the voltage sensor was reported as a site-mediating redox modulation of the channels. Recent structural insights reveal potential interactions between this linker and the Ca2+-binding loop of the third EF-hand of calmodulin (CaM), which embraces an antiparallel fork formed by the C-terminal helices A and B, constituting the calcium responsive domain (CRD). We found that precluding Ca2+ binding to the EF3 hand, but not to EF1, EF2, or EF4 hands, abolishes oxidation-induced enhancement of KV7.4 currents. Monitoring FRET (Fluorescence Resonance Energy Transfer) between helices A and B using purified CRDs tagged with fluorescent proteins, we observed that S2S3 peptides cause a reversal of the signal in the presence of Ca2+ but have no effect in the absence of this cation or if the peptide is oxidized. The capacity of loading EF3 with Ca2+ is essential for this reversal of the FRET signal, whereas the consequences of obliterating Ca2+ binding to EF1, EF2, or EF4 are negligible. Furthermore, we show that EF3 is critical for translating Ca2+ signals to reorient the AB fork. Our data are consistent with the proposal that oxidation of cysteine residues in the S2S3 loop relieves KV7 channels from a constitutive inhibition imposed by interactions between the EF3 hand of CaM which is crucial for this signaling.Ministerio de Ciencia e Innovacion PID2021-128286NB-100Wellcome Trust 212302/Z/18/ZMedical Research Centre MR/P015727/1Eusko Jaurlaritza IT1707-22 Ekonomiaren Garapen eta Lehiakortasun Saila, Eusko Jaurlaritza BG2019Ministerio de Ciencia e Innovacion RTI2018-097839-B-100Ministerio de Ciencia e Innovacion RTI2018-101269-B-I00Eusko Jaurlaritza IT1165-19 Ekonomiaren Garapen eta Lehiakortasun Saila,Eusko Jaurlaritza KK-2020/00110Eusko Jaurlaritza PRE_2018-2_0082Eusko Jaurlaritza POS_2021_1_0017Eusko Jaurlaritza PRE_2018-2_0126eLife Sciences202320232023info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10810/60885reponame:Addi. Archivo Digital para la Docencia y la Investigacióninstname:Universidad del País VascoInglésinfo:eu-repo/grantAgreement/MICINN/PID2021-128286NB-100/info:eu-repo/grantAgreement/MICIU/RTI2018‐097839-B-100/info:eu-repo/grantAgreement/MICIU/RTI2018-101269-B-I00/https://elifesciences.org/articles/81961info:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by/3.0/es/Copyright Nuñez et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.Atribución 3.0 Españaoai:addi.ehu.eus:10810/608852026-06-18T09:23:17Z
dc.title.none.fl_str_mv Redox regulation of KV7 channels through EF3 hand of calmodulin
title Redox regulation of KV7 channels through EF3 hand of calmodulin
spellingShingle Redox regulation of KV7 channels through EF3 hand of calmodulin
Nuñez Viadero, Eider
KCNQ
calmodulin
redox
calcium
EF-hand
signal transduction
E
coli
title_short Redox regulation of KV7 channels through EF3 hand of calmodulin
title_full Redox regulation of KV7 channels through EF3 hand of calmodulin
title_fullStr Redox regulation of KV7 channels through EF3 hand of calmodulin
title_full_unstemmed Redox regulation of KV7 channels through EF3 hand of calmodulin
title_sort Redox regulation of KV7 channels through EF3 hand of calmodulin
dc.creator.none.fl_str_mv Nuñez Viadero, Eider
Jones, Frederick
Muguruza Montero, Arantza
Urrutia Iñiguez, Janire
Aguado Martínez, Alejandra
Malo de la Fuente, Covadonga
Bernardo Seisdedos, Ganeko
Domene, Carmen
Millet Aguilar-Galindo, Oscar
Gamper, Nikita
Villarroel Muñoz, Álvaro
author Nuñez Viadero, Eider
author_facet Nuñez Viadero, Eider
Jones, Frederick
Muguruza Montero, Arantza
Urrutia Iñiguez, Janire
Aguado Martínez, Alejandra
Malo de la Fuente, Covadonga
Bernardo Seisdedos, Ganeko
Domene, Carmen
Millet Aguilar-Galindo, Oscar
Gamper, Nikita
Villarroel Muñoz, Álvaro
author_role author
author2 Jones, Frederick
Muguruza Montero, Arantza
Urrutia Iñiguez, Janire
Aguado Martínez, Alejandra
Malo de la Fuente, Covadonga
Bernardo Seisdedos, Ganeko
Domene, Carmen
Millet Aguilar-Galindo, Oscar
Gamper, Nikita
Villarroel Muñoz, Álvaro
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv KCNQ
calmodulin
redox
calcium
EF-hand
signal transduction
E
coli
topic KCNQ
calmodulin
redox
calcium
EF-hand
signal transduction
E
coli
description Neuronal KV7 channels, important regulators of cell excitability, are among the most sensitive proteins to reactive oxygen species. The S2S3 linker of the voltage sensor was reported as a site-mediating redox modulation of the channels. Recent structural insights reveal potential interactions between this linker and the Ca2+-binding loop of the third EF-hand of calmodulin (CaM), which embraces an antiparallel fork formed by the C-terminal helices A and B, constituting the calcium responsive domain (CRD). We found that precluding Ca2+ binding to the EF3 hand, but not to EF1, EF2, or EF4 hands, abolishes oxidation-induced enhancement of KV7.4 currents. Monitoring FRET (Fluorescence Resonance Energy Transfer) between helices A and B using purified CRDs tagged with fluorescent proteins, we observed that S2S3 peptides cause a reversal of the signal in the presence of Ca2+ but have no effect in the absence of this cation or if the peptide is oxidized. The capacity of loading EF3 with Ca2+ is essential for this reversal of the FRET signal, whereas the consequences of obliterating Ca2+ binding to EF1, EF2, or EF4 are negligible. Furthermore, we show that EF3 is critical for translating Ca2+ signals to reorient the AB fork. Our data are consistent with the proposal that oxidation of cysteine residues in the S2S3 loop relieves KV7 channels from a constitutive inhibition imposed by interactions between the EF3 hand of CaM which is crucial for this signaling.
publishDate 2023
dc.date.none.fl_str_mv 2023
2023
2023
dc.type.none.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/10810/60885
url http://hdl.handle.net/10810/60885
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv info:eu-repo/grantAgreement/MICINN/PID2021-128286NB-100/
info:eu-repo/grantAgreement/MICIU/RTI2018‐097839-B-100/
info:eu-repo/grantAgreement/MICIU/RTI2018-101269-B-I00/
https://elifesciences.org/articles/81961
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
http://creativecommons.org/licenses/by/3.0/es/
Atribución 3.0 España
eu_rights_str_mv openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by/3.0/es/
Atribución 3.0 España
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv eLife Sciences
publisher.none.fl_str_mv eLife Sciences
dc.source.none.fl_str_mv reponame:Addi. Archivo Digital para la Docencia y la Investigación
instname:Universidad del País Vasco
instname_str Universidad del País Vasco
reponame_str Addi. Archivo Digital para la Docencia y la Investigación
collection Addi. Archivo Digital para la Docencia y la Investigación
repository.name.fl_str_mv
repository.mail.fl_str_mv
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