Structural determinants of 5′,6′-epoxyeicosatrienoic acid binding to and activation of TRPV4 channel

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• dc.contributor.author Berna Erro, Alejandroca
• dc.contributor.author Izquierdo Serra, Mercèca
• dc.contributor.author Sepúlveda, Romina V.ca
• dc.contributor.author Rubio Moscardó, Fannyca
• dc.contributor.author Doñate-Macián, Pauca
• dc.contributor.author Serra Pascual, Selma A., 1981-ca
• dc.contributor.author Carrillo García, Julia, 1993-ca
• dc.contributor.author Perálvarez Marín, Alexca
• dc.contributor.author González Nilo, Fernandoca
• dc.contributor.author Fernández-Fernández, José Manuel, 1967-ca
• dc.contributor.author Valverde, M. A. (Miguel Ángel), 1963-ca
• dc.date.accessioned 2017-11-27T10:12:17Z
• dc.date.available 2017-11-27T10:12:17Z
• dc.date.issued 2017
• dc.description.abstract TRPV4 cation channel activation by cytochrome P450-mediated derivatives of arachidonic acid (AA), epoxyeicosatrienoic acids (EETs), constitute a major mechanisms of endothelium-derived vasodilatation. Besides, TRPV4 mechano/osmosensitivity depends on phospholipase A2 (PLA2) activation and subsequent production of AA and EETs. However, the lack of evidence for a direct interaction of EETs with TRPV4 together with claims of EET-independent mechanical activation of TRPV4 has cast doubts on the validity of this mechanism. We now report: 1) The identification of an EET-binding pocket that specifically mediates TRPV4 activation by 5′,6′-EET, AA and hypotonic cell swelling, thereby suggesting that all these stimuli shared a common structural target within the TRPV4 channel; and 2) A structural insight into the gating of TRPV4 by a natural agonist (5′,6′-EET) in which K535 plays a crucial role, as mutant TRPV4-K535A losses binding of and gating by EET, without affecting GSK1016790A, 4α-phorbol 12,13-didecanoate and heat mediated channel activation. Together, our data demonstrates that the mechano- and osmotransducing messenger EET gates TRPV4 by a direct action on a site formed by residues from the S2-S3 linker, S4 and S4-S5 linker.
• dc.description.sponsorship The research is supported by awards from the Spanish Ministry of Economy and Competitiveness (Grants SAF2015-69762-R to M.A.V. and J.M.F.-F., and MDM-2014-0370 through the “María de Maeztu” Programme for Units of Excellence in R&D to “Departament de Ciències Experimentals i de la Salut”), and FEDER Funds (Fondo Europeo de Desarrollo Regional). M.I.-S. holds a “Juan de la Cierva-Formación” Fellowship funded by the Spanish Ministry of Economy and Competitiveness. FGN acknowledge the support of FONDECYT Grant 1170733 and The Centro Interdisciplinario de Neurociencia de Valparaíso (CINV) is a Millennium Institute supported by the Millennium Scientific Initiative of the Ministerio de Economía, Fomento y Turismo. R.V.S. is funded by CONICYT PCHA/Doctorado Nacional 2013-21130631 fellowship
• dc.format.mimetype application/pdfca
• dc.identifier.citation Berna-Erro A, Izquierdo-Serra M, Sepúlveda RV, Rubio-Moscardo F, Doñate-Macián P, Serra SA et al. Structural determinants of 5′,6′-epoxyeicosatrienoic acid binding to and activation of TRPV4 channel. Sci Rep. 2017 Sep 5;7(1):10522. DOI: 10.1038/s41598-017-11274-1
• dc.identifier.doi http://dx.doi.org/10.1038/s41598-017-11274-1
• dc.identifier.issn 2045-2322
• dc.identifier.uri http://hdl.handle.net/10230/33344
• dc.language.iso eng
• dc.publisher Nature Publishing Groupca
• dc.relation.ispartof Scientific Reports. 2017 Sep 5;7(1):10522
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2015-69762-R
• dc.rights © Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Ion channel signalling
• dc.subject.keyword Vasodilation
• dc.title Structural determinants of 5′,6′-epoxyeicosatrienoic acid binding to and activation of TRPV4 channelca
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion