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

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dc.contributor.authorBerna-Erro, A.
dc.contributor.authorIzquierdo-Serra, M.
dc.contributor.authorSepúlveda, R.V.
dc.contributor.authorRubio-Moscardo, F.
dc.contributor.authorDoñate-Macián, P.
dc.contributor.authorSerra, S.A.
dc.contributor.authorCarrillo-Garcia, J.
dc.contributor.authorPerálvarez-Marín, A.
dc.contributor.authorGonzález-Nilo, F.
dc.contributor.authorFernández-Fernández, J.M.
dc.contributor.authorValverde, M.A.
dc.date.accessioned2018-02-01T20:29:52Z
dc.date.available2018-02-01T20:29:52Z
dc.date.issued2017-12
dc.descriptionIndexación: Web of Science; Scopus.es_CL
dc.description.abstractTRPV4 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.es_CL
dc.description.urihttp://recursosbiblioteca.unab.cl:2226/articles/s41598-017-11274-1.pdf
dc.identifier.citationScientific Reports. Volume 7, Issue 1, 1 December 2017, Article number 10522es_CL
dc.identifier.issn2045-2322
dc.identifier.otherDOI: 10.1038/s41598-017-11274-1
dc.identifier.urihttp://repositorio.unab.cl/xmlui/handle/ria/5244
dc.language.isoenes_CL
dc.publisherNature Publishing Groupes_CL
dc.rights.licenseAttribution 4.0 International (CC BY 4.0)
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectHEAT-EVOKED ACTIVATIONes_CL
dc.subjectCATION CHANNELes_CL
dc.subjectEPOXYEICOSATRIENOIC ACIDSes_CL
dc.subjectION-CHANNELes_CL
dc.subjectPHOSPHOLIPASE A(2)es_CL
dc.subjectENDOTHELIAL-CELLSes_CL
dc.subjectFUNCTIONAL-ROLEes_CL
dc.subjectVR-OACes_CL
dc.subjectMICEes_CL
dc.subjectDIFFERENTIATIONes_CL
dc.titleStructural determinants of 5′,6′-epoxyeicosatrienoic acid binding to and activation of TRPV4 channeles_CL
dc.typeArtículoes_CL
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