The immunosuppressant macrolide tacrolimus activates cold-sensing TRPM8 channels

TRPM8 is a polymodal, nonselective cation channel activated by cold temperature and cooling agents that plays a critical role in the detection of environmental cold. We found that TRPM8 is a pharmacological target of tacrolimus (FK506), a macrolide immunosuppressant with several clinical uses, inclu...

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Autores: Arcas, José Miguel, González, Alejandro, Gers-Barlag, Katharina, González-González, Omar, Bech, Federico, Demirkhanyan, Lusine, Zakharian, Eleonora, Belmonte, Carlos, Gomis, Ana, Viana, Félix
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2019
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/218000
Acceso en línea:http://hdl.handle.net/10261/218000
Access Level:acceso abierto
Palabra clave:Neuroimmune
Cornea
Pain
Thermoreceptor
Trigeminal
TRP channel
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spelling The immunosuppressant macrolide tacrolimus activates cold-sensing TRPM8 channelsArcas, José MiguelGonzález, AlejandroGers-Barlag, KatharinaGonzález-González, OmarBech, FedericoDemirkhanyan, LusineZakharian, EleonoraBelmonte, CarlosGomis, AnaViana, FélixNeuroimmuneCorneaPainThermoreceptorTrigeminalTRP channelTRPM8 is a polymodal, nonselective cation channel activated by cold temperature and cooling agents that plays a critical role in the detection of environmental cold. We found that TRPM8 is a pharmacological target of tacrolimus (FK506), a macrolide immunosuppressant with several clinical uses, including the treatment of organ rejection following transplants, treatment of atopic dermatitis, and dry eye disease. Tacrolimus is an inhibitor of the phosphatase calcineurin, an action shared with cyclosporine. Tacrolimus activates TRPM8 channels in different species, including humans, and sensitizes their response to cold temperature by inducing a leftward shift in the voltage-dependent activation curve. The effects of tacrolimus on purified TRPM8 in lipid bilayers demonstrates conclusively that it has a direct gating effect. Moreover, the lack of effect of cyclosporine rules out the canonical signaling pathway involving the phosphatase calcineurin. Menthol (TRPM8-Y745H)- and icilin (TRPM8-N799A)-insensitive mutants were also activated by tacrolimus, suggesting a different binding site. In cultured mouse DRG neurons, tacrolimus evokes an increase in intracellular calcium almost exclusively in cold-sensitive neurons, and these responses were drastically blunted in Trpm8 KO mice or after the application of TRPM8 antagonists. Cutaneous and corneal cold thermoreceptor endings are also activated by tacrolimus, and tacrolimus solutions trigger blinking and cold-evoked behaviors. Together, our results identify TRPM8 channels in sensory neurons as molecular targets of the immunosuppressant tacrolimus. The actions of tacrolimus on TRPM8 resemble those of menthol but likely involve interactions with other channel residues.This work was supported by Project SAF2016-77233-R and cofinanced by the European Regional Development Fund and the Severo Ochoa Programme for Centres of Excellence in R&D SEV- 2013-0317. J.M.A. was supported by Spanish Ministry of Education and Science predoctoral fellowships. K.G.-B. was supported by the International PhD Fellowships Program La Caixa-Severo Ochoa, Call 2015.Peer reviewedSociety for NeuroscienceMinisterio de Economía y Competitividad (España)European CommissionMinisterio de Educación y Ciencia (España)Fundación la CaixaConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202020202019info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/218000reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2016-77233-Rinfo:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SEV-2013-0317https://doi.org/10.1523/JNEUROSCI.1726-18.2018Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2180002026-05-22T06:33:51Z
dc.title.none.fl_str_mv The immunosuppressant macrolide tacrolimus activates cold-sensing TRPM8 channels
title The immunosuppressant macrolide tacrolimus activates cold-sensing TRPM8 channels
spellingShingle The immunosuppressant macrolide tacrolimus activates cold-sensing TRPM8 channels
Arcas, José Miguel
Neuroimmune
Cornea
Pain
Thermoreceptor
Trigeminal
TRP channel
title_short The immunosuppressant macrolide tacrolimus activates cold-sensing TRPM8 channels
title_full The immunosuppressant macrolide tacrolimus activates cold-sensing TRPM8 channels
title_fullStr The immunosuppressant macrolide tacrolimus activates cold-sensing TRPM8 channels
title_full_unstemmed The immunosuppressant macrolide tacrolimus activates cold-sensing TRPM8 channels
title_sort The immunosuppressant macrolide tacrolimus activates cold-sensing TRPM8 channels
dc.creator.none.fl_str_mv Arcas, José Miguel
González, Alejandro
Gers-Barlag, Katharina
González-González, Omar
Bech, Federico
Demirkhanyan, Lusine
Zakharian, Eleonora
Belmonte, Carlos
Gomis, Ana
Viana, Félix
author Arcas, José Miguel
author_facet Arcas, José Miguel
González, Alejandro
Gers-Barlag, Katharina
González-González, Omar
Bech, Federico
Demirkhanyan, Lusine
Zakharian, Eleonora
Belmonte, Carlos
Gomis, Ana
Viana, Félix
author_role author
author2 González, Alejandro
Gers-Barlag, Katharina
González-González, Omar
Bech, Federico
Demirkhanyan, Lusine
Zakharian, Eleonora
Belmonte, Carlos
Gomis, Ana
Viana, Félix
author2_role author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Economía y Competitividad (España)
European Commission
Ministerio de Educación y Ciencia (España)
Fundación la Caixa
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Neuroimmune
Cornea
Pain
Thermoreceptor
Trigeminal
TRP channel
topic Neuroimmune
Cornea
Pain
Thermoreceptor
Trigeminal
TRP channel
description TRPM8 is a polymodal, nonselective cation channel activated by cold temperature and cooling agents that plays a critical role in the detection of environmental cold. We found that TRPM8 is a pharmacological target of tacrolimus (FK506), a macrolide immunosuppressant with several clinical uses, including the treatment of organ rejection following transplants, treatment of atopic dermatitis, and dry eye disease. Tacrolimus is an inhibitor of the phosphatase calcineurin, an action shared with cyclosporine. Tacrolimus activates TRPM8 channels in different species, including humans, and sensitizes their response to cold temperature by inducing a leftward shift in the voltage-dependent activation curve. The effects of tacrolimus on purified TRPM8 in lipid bilayers demonstrates conclusively that it has a direct gating effect. Moreover, the lack of effect of cyclosporine rules out the canonical signaling pathway involving the phosphatase calcineurin. Menthol (TRPM8-Y745H)- and icilin (TRPM8-N799A)-insensitive mutants were also activated by tacrolimus, suggesting a different binding site. In cultured mouse DRG neurons, tacrolimus evokes an increase in intracellular calcium almost exclusively in cold-sensitive neurons, and these responses were drastically blunted in Trpm8 KO mice or after the application of TRPM8 antagonists. Cutaneous and corneal cold thermoreceptor endings are also activated by tacrolimus, and tacrolimus solutions trigger blinking and cold-evoked behaviors. Together, our results identify TRPM8 channels in sensory neurons as molecular targets of the immunosuppressant tacrolimus. The actions of tacrolimus on TRPM8 resemble those of menthol but likely involve interactions with other channel residues.
publishDate 2019
dc.date.none.fl_str_mv 2019
2020
2020
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/10261/218000
url http://hdl.handle.net/10261/218000
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#
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2016-77233-R
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SEV-2013-0317
https://doi.org/10.1523/JNEUROSCI.1726-18.2018
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Society for Neuroscience
publisher.none.fl_str_mv Society for Neuroscience
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
repository.mail.fl_str_mv
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score 15,812429

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