Anandamide and arachidonic acid use epoxyeicosatrienoic acids to activate TRPV4 channels

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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.