Structural determinants of 5′,6′-epoxyeicosatrienoic acid binding to and activation of TRPV4 channel
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Fecha
2017-12
Profesor/a Guía
Facultad/escuela
Idioma
en
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Editor
Nature Publishing Group
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Licencia CC
Attribution 4.0 International (CC BY 4.0)
Licencia CC
https://creativecommons.org/licenses/by/4.0/
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.
Notas
Indexación: Web of Science; Scopus.
Palabras clave
HEAT-EVOKED ACTIVATION, CATION CHANNEL, EPOXYEICOSATRIENOIC ACIDS, ION-CHANNEL, PHOSPHOLIPASE A(2), ENDOTHELIAL-CELLS, FUNCTIONAL-ROLE, VR-OAC, MICE, DIFFERENTIATION
Citación
Scientific Reports. Volume 7, Issue 1, 1 December 2017, Article number 10522