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Grant support

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 Maria de Maeztu Programme for Units of Excellence in R&D to Departament de Ciencies Experimentals i de la Salut), and FEDER Funds (Fondo Europeo de Desarrollo Regional). M.I.-S. holds a Juan de la Cierva-Formacion 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 Valparai'so (CINV) is a Millennium Institute supported by the Millennium Scientific Initiative of the Ministerio de Economia, Fomento y Turismo. R.V.S. is funded by CONICYT PCHA/Doctorado Nacional 2013-21130631 fellowship.

Analysis of institutional authors

Izquierdo-Serra, MAuthor
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Article

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

Publicated to:Scientific Reports. 7 (10522): 10522- - 2017-09-05 7(10522), DOI: 10.1038/s41598-017-11274-1

Authors: Berna-Erro, A; Izquierdo-Serra, M; Sepulveda, RV; Rubio-Moscardo, F; Donate-Macian, P; Serra, SA; Carrillo-Garcia, J; Peralvarez-Marin, A; Gonzalez-Nilo, F; Fernandez-Fernandez, JM; Valverde, MA

Affiliations

Univ Andres Bello, Ctr Bioinformat & Integrat Biol, Fac Ciencias Biol, Av Republ 239, Santiago, Chile - Author
Univ Autonoma Barcelona, Dept Bioquim & Biol Mol, Ctr Estudis Biofis, Unitat Biofis, Bellaterra 08193, Spain - Author
Univ Pompeu Fabra, Dept Expt & Hlth Sci, Lab Mol Physiol, Barcelona, Spain - Author
Univ Valparaiso, Fac Ciencias, Ctr Interdisciplinario Neurociencia Valparaiso, Valparaiso 2366103, Chile - Author

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 A(2) (PLA(2)) 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, 4 alpha-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.

Keywords
Cation channelDifferentiationEndothelial-cellsEpoxyeicosatrienoic acidsFunctional-roleHeat-evoked activationIon-channelMicePhospholipase a(2)Vr-oac

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Scientific Reports due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2017, it was in position 12/64, thus managing to position itself as a Q1 (Primer Cuartil), in the category Multidisciplinary Sciences.

From a relative perspective, and based on the normalized impact indicator calculated from World Citations provided by WoS (ESI, Clarivate), it yields a value for the citation normalization relative to the expected citation rate of: 1.17. This indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: ESI Nov 14, 2024)

This information is reinforced by other indicators of the same type, which, although dynamic over time and dependent on the set of average global citations at the time of their calculation, consistently position the work at some point among the top 50% most cited in its field:

  • Field Citation Ratio (FCR) from Dimensions: 12.88 (source consulted: Dimensions May 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-05-16, the following number of citations:

  • WoS: 31
  • Scopus: 62
  • OpenCitations: 59
Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-05-16:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 91.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 91 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 1.85.
  • The number of mentions on the social network X (formerly Twitter): 3 (Altmetric).

It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

  • The work has been submitted to a journal whose editorial policy allows open Open Access publication.
Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: Chile.