KCNE4-dependent modulation of Kv1.3 pharmacology

The voltage-dependent potassium channel Kv1.3 is a promising therapeutic target for the treatment of autoimmune and chronic inflammatory disorders. Kv1.3 blockers are effective in treating multiple sclerosis (fampridine) and psoriasis (dalazatide). However, most Kv1.3 pharmacological antagonists are...

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Autores: Sastre, Daniel, Colomer-Molera, Magalí, Benito-Bueno, Ángela de, Valenzuela, Carmen, Fernández-Ballester, Gregorio, Felipe, Antonio
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2024
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/363770
Acceso en línea:http://hdl.handle.net/10261/363770
Access Level:acceso abierto
Palabra clave:Potassium channels
Leukocytes
Autoimmune diseases
Oligomeric complex
Regulatory subunits
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spelling KCNE4-dependent modulation of Kv1.3 pharmacologySastre, DanielColomer-Molera, MagalíBenito-Bueno, Ángela deValenzuela, CarmenFernández-Ballester, GregorioFelipe, AntonioPotassium channelsLeukocytesAutoimmune diseasesOligomeric complexRegulatory subunitsThe voltage-dependent potassium channel Kv1.3 is a promising therapeutic target for the treatment of autoimmune and chronic inflammatory disorders. Kv1.3 blockers are effective in treating multiple sclerosis (fampridine) and psoriasis (dalazatide). However, most Kv1.3 pharmacological antagonists are not specific enough, triggering potential side effects and limiting their therapeutic use. Functional Kv are oligomeric complexes in which the presence of ancillary subunits shapes their function and pharmacology. In leukocytes, Kv1.3 associates with KCNE4, which reduces the surface abundance and enhances the inactivation of the channel. This mechanism exerts profound consequences on Kv1.3-related physiological responses. Because KCNE peptides alter the pharmacology of Kv channels, we studied the effects of KCNE4 on Kv1.3 pharmacology to gain insights into pharmacological approaches. To that end, we used margatoxin, which binds the channel pore from the extracellular space, and Psora-4, which blocks the channel from the intracellular side. While KCNE4 apparently did not alter the affinity of either margatoxin or Psora-4, it slowed the inhibition kinetics of the latter in a stoichiometry-dependent manner. The results suggested changes in the Kv1.3 architecture in the presence of KCNE4. The data indicated that while the outer part of the channel mouth remains unaffected, KCNE4 disturbs the intracellular architecture of the complex. Various leukocyte types expressing different Kv1.3/KCNE4 configurations participate in the immune response. Our data provide evidence that the presence of these variable architectures, which affect both the structure of the complex and their pharmacology, should be considered when developing putative therapeutic approaches.Supported by the Ministerio de Ciencia e Innovación (MICINN/AEI), Spain (PID2020-112647RB-I00 and PID2023-148085OB-I00 (to AF), PID2022-137214OB-C21 (to CV) and 10.13039/501100011033) and European Regional Development Fund (FEDER).Peer reviewedElsevierMinisterio de Ciencia, Innovación y Universidades (España)Agencia Estatal de Investigación (España)Ministerio de Ciencia e Innovación (España)European CommissionConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202420242024info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/363770reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-112647RB-I00info:eu-repo/grantAgreement/AEI//PID2023-148085OB-I00info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2022-137214OB-C21https://doi.org/10.1016/j.bcp.2024.116368Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3637702026-05-22T06:33:51Z
dc.title.none.fl_str_mv KCNE4-dependent modulation of Kv1.3 pharmacology
title KCNE4-dependent modulation of Kv1.3 pharmacology
spellingShingle KCNE4-dependent modulation of Kv1.3 pharmacology
Sastre, Daniel
Potassium channels
Leukocytes
Autoimmune diseases
Oligomeric complex
Regulatory subunits
title_short KCNE4-dependent modulation of Kv1.3 pharmacology
title_full KCNE4-dependent modulation of Kv1.3 pharmacology
title_fullStr KCNE4-dependent modulation of Kv1.3 pharmacology
title_full_unstemmed KCNE4-dependent modulation of Kv1.3 pharmacology
title_sort KCNE4-dependent modulation of Kv1.3 pharmacology
dc.creator.none.fl_str_mv Sastre, Daniel
Colomer-Molera, Magalí
Benito-Bueno, Ángela de
Valenzuela, Carmen
Fernández-Ballester, Gregorio
Felipe, Antonio
author Sastre, Daniel
author_facet Sastre, Daniel
Colomer-Molera, Magalí
Benito-Bueno, Ángela de
Valenzuela, Carmen
Fernández-Ballester, Gregorio
Felipe, Antonio
author_role author
author2 Colomer-Molera, Magalí
Benito-Bueno, Ángela de
Valenzuela, Carmen
Fernández-Ballester, Gregorio
Felipe, Antonio
author2_role author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Ciencia, Innovación y Universidades (España)
Agencia Estatal de Investigación (España)
Ministerio de Ciencia e Innovación (España)
European Commission
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Potassium channels
Leukocytes
Autoimmune diseases
Oligomeric complex
Regulatory subunits
topic Potassium channels
Leukocytes
Autoimmune diseases
Oligomeric complex
Regulatory subunits
description The voltage-dependent potassium channel Kv1.3 is a promising therapeutic target for the treatment of autoimmune and chronic inflammatory disorders. Kv1.3 blockers are effective in treating multiple sclerosis (fampridine) and psoriasis (dalazatide). However, most Kv1.3 pharmacological antagonists are not specific enough, triggering potential side effects and limiting their therapeutic use. Functional Kv are oligomeric complexes in which the presence of ancillary subunits shapes their function and pharmacology. In leukocytes, Kv1.3 associates with KCNE4, which reduces the surface abundance and enhances the inactivation of the channel. This mechanism exerts profound consequences on Kv1.3-related physiological responses. Because KCNE peptides alter the pharmacology of Kv channels, we studied the effects of KCNE4 on Kv1.3 pharmacology to gain insights into pharmacological approaches. To that end, we used margatoxin, which binds the channel pore from the extracellular space, and Psora-4, which blocks the channel from the intracellular side. While KCNE4 apparently did not alter the affinity of either margatoxin or Psora-4, it slowed the inhibition kinetics of the latter in a stoichiometry-dependent manner. The results suggested changes in the Kv1.3 architecture in the presence of KCNE4. The data indicated that while the outer part of the channel mouth remains unaffected, KCNE4 disturbs the intracellular architecture of the complex. Various leukocyte types expressing different Kv1.3/KCNE4 configurations participate in the immune response. Our data provide evidence that the presence of these variable architectures, which affect both the structure of the complex and their pharmacology, should be considered when developing putative therapeutic approaches.
publishDate 2024
dc.date.none.fl_str_mv 2024
2024
2024
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/363770
url http://hdl.handle.net/10261/363770
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-112647RB-I00
info:eu-repo/grantAgreement/AEI//PID2023-148085OB-I00
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2022-137214OB-C21
https://doi.org/10.1016/j.bcp.2024.116368
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
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