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Anandamide and arachidonic acid use epoxyeicosatrienoic acids to activate TRPV4 channels

Nature volume 424, pages 434–438 (2003)Cite this article

Abstract

TRPV4 is a widely expressed cation channel of the ‘transient receptor potential’ (TRP) family1 that is related to the vanilloid receptor VR1 (TRPV1). It functions as a Ca2+ entry channel2 and displays remarkable gating promiscuity by responding to both physical stimuli (cell swelling, innoxious heat2,3,4,5,6,7) and the synthetic ligand 4αPDD8. An endogenous ligand for this channel has not yet been identified. Here we show that the endocannabinoid anandamide and its metabolite arachidonic acid activate TRPV4 in an indirect way involving the cytochrome P450 epoxygenase-dependent formation of epoxyeicosatrienoic acids. Application of 5′,6′-epoxyeicosatrienoic acid at submicromolar concentrations activates TRPV4 in a membrane-delimited manner and causes Ca2+ influx through TRPV4-like channels in vascular endothelial cells. Activation of TRPV4 in vascular endothelial cells might therefore contribute to the relaxant effects of endocannabinoids and their P450 epoxygenase-dependent metabolites on vascular tone9,10,11,12.

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Figure 1: Effect of AA on [Ca2+]i and currents in TRPV4-expressing HEK-293 cells.
Figure 2: AEA and 2-AG increase [Ca2+]i and activate currents in TRPV4-transfected cells.
Figure 3: Unravelling the activation cascade of TRPV4.
Figure 4: Activation of TRPV4 by EETs.
Figure 5: 5′,6′-EET-induced increase of [Ca2+]i and activation of a TRPV4-like current in native endothelial cells from mouse aorta.

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Acknowledgements

We thank V. Flockerzi and C. D. Benham for comments, and V. Flockerzi and U. Wissenbach for providing the mTRP12 clone (mTRPV4). This work was supported by the Belgian Federal Government, the Flemish Government and the Onderzoeksraad KU Leuven (Interuniversity Poles of Attraction Program, IUAP). T.V. is a postdoctoral Fellow of the Fund for Scientific Research–Flanders (Belgium) (FWO–Vlaanderen).

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  1. Hiroyuki Watanabe and Joris Vriens: These authors contributed equally to this work

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  1. Department of Physiology, Campus Gasthuisberg, KU Leuven, B-3000, Leuven, Belgium

    Hiroyuki Watanabe, Joris Vriens, Jean Prenen, Guy Droogmans, Thomas Voets & Bernd Nilius

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  1. Hiroyuki Watanabe
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Correspondence to Bernd Nilius.

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Watanabe, H., Vriens, J., Prenen, J. et al. Anandamide and arachidonic acid use epoxyeicosatrienoic acids to activate TRPV4 channels. Nature 424, 434–438 (2003). https://doi.org/10.1038/nature01807

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