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

Alejandro Berna-Erro, Mercè Izquierdo-Serra, Romina V. Sepúlveda, Fanny Rubio-Moscardo, Pau Doñate-Macián, Selma A. Serra, Julia Carrillo-Garcia, Alex Perálvarez-Marín, Fernando González-Nilo, José M. Fernández-Fernández, Miguel A. Valverde

Resultado de la investigación: Article

13 Citas (Scopus)

Resumen

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.

Idioma originalEnglish
Número de artículo10522
PublicaciónScientific Reports
Volumen7
N.º1
DOI
EstadoPublished - 1 dic 2017

Huella dactilar

Arachidonic Acid
Phospholipases A2
Vasodilation
Cytochrome P-450 Enzyme System
Endothelium
Cations
Hot Temperature
Acids
5,6-epoxy-8,11,14-eicosatrienoic acid

ASJC Scopus subject areas

  • General

Citar esto

Berna-Erro, A., Izquierdo-Serra, M., Sepúlveda, R. V., Rubio-Moscardo, F., Doñate-Macián, P., Serra, S. A., ... Valverde, M. A. (2017). Structural determinants of 5′,6′-epoxyeicosatrienoic acid binding to and activation of TRPV4 channel. Scientific Reports, 7(1), [10522]. https://doi.org/10.1038/s41598-017-11274-1
Berna-Erro, Alejandro ; Izquierdo-Serra, Mercè ; Sepúlveda, Romina V. ; Rubio-Moscardo, Fanny ; Doñate-Macián, Pau ; Serra, Selma A. ; Carrillo-Garcia, Julia ; Perálvarez-Marín, Alex ; González-Nilo, Fernando ; Fernández-Fernández, José M. ; Valverde, Miguel A. / Structural determinants of 5′,6′-epoxyeicosatrienoic acid binding to and activation of TRPV4 channel. En: Scientific Reports. 2017 ; Vol. 7, N.º 1.
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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.",
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Berna-Erro, A, Izquierdo-Serra, M, Sepúlveda, RV, Rubio-Moscardo, F, Doñate-Macián, P, Serra, SA, Carrillo-Garcia, J, Perálvarez-Marín, A, González-Nilo, F, Fernández-Fernández, JM & Valverde, MA 2017, 'Structural determinants of 5′,6′-epoxyeicosatrienoic acid binding to and activation of TRPV4 channel', Scientific Reports, vol. 7, n.º 1, 10522. https://doi.org/10.1038/s41598-017-11274-1

Structural determinants of 5′,6′-epoxyeicosatrienoic acid binding to and activation of TRPV4 channel. / Berna-Erro, Alejandro; Izquierdo-Serra, Mercè; Sepúlveda, Romina V.; Rubio-Moscardo, Fanny; Doñate-Macián, Pau; Serra, Selma A.; Carrillo-Garcia, Julia; Perálvarez-Marín, Alex; González-Nilo, Fernando; Fernández-Fernández, José M.; Valverde, Miguel A.

En: Scientific Reports, Vol. 7, N.º 1, 10522, 01.12.2017.

Resultado de la investigación: Article

TY - JOUR

T1 - Structural determinants of 5′,6′-epoxyeicosatrienoic acid binding to and activation of TRPV4 channel

AU - Berna-Erro, Alejandro

AU - Izquierdo-Serra, Mercè

AU - Sepúlveda, Romina V.

AU - Rubio-Moscardo, Fanny

AU - Doñate-Macián, Pau

AU - Serra, Selma A.

AU - Carrillo-Garcia, Julia

AU - Perálvarez-Marín, Alex

AU - González-Nilo, Fernando

AU - Fernández-Fernández, José M.

AU - Valverde, Miguel A.

PY - 2017/12/1

Y1 - 2017/12/1

N2 - 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.

AB - 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.

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Berna-Erro A, Izquierdo-Serra M, Sepúlveda RV, Rubio-Moscardo F, Doñate-Macián P, Serra SA y otros. Structural determinants of 5′,6′-epoxyeicosatrienoic acid binding to and activation of TRPV4 channel. Scientific Reports. 2017 dic 1;7(1). 10522. https://doi.org/10.1038/s41598-017-11274-1