1. Department of Physiology, Campus Gasthuisberg, KU Leuven, B-3000 Leuven, Belgium
2. These authors contributed equally to this work

Correspondence to: Bernd Nilius¹ Correspondence and requests for materials should be addressed to B.N. (Email: bernd.nilius@med.kuleuven.ac.be).

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 heat^{2, 3, 4, 5, 6, 7}) and the synthetic ligand 4PDD⁸. 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 tone^{9, 10, 11, 12}.