Anandamide and arachidonic acid use epoxyeicosatrienoic acids to activate TRPV4 channels.

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 0410462 Publication Model: Print Cited Medium: Internet ISSN: 1476-4687 (Electronic) Linking ISSN: 00280836 NLM ISO Abbreviation: Nature Subsets: MEDLINE

Publication: Basingstoke : Nature Publishing Group
Original Publication: London, Macmillan Journals ltd.

Cation Transport Proteins*; 8,11,14-Eicosatrienoic Acid/*metabolism ; Arachidonic Acid/*pharmacology ; Arachidonic Acids/*pharmacology ; Ion Channels/*metabolism; 8,11,14-Eicosatrienoic Acid/analogs & derivatives ; 8,11,14-Eicosatrienoic Acid/pharmacology ; Animals ; Aorta ; Calcium/metabolism ; Cannabinoid Receptor Modulators ; Cell Line ; Electrophysiology ; Endocannabinoids ; Endothelium, Vascular/drug effects ; Endothelium, Vascular/metabolism ; Humans ; Ion Channel Gating/drug effects ; Mice ; Polyunsaturated Alkamides ; TRPV Cation Channels

TRPV4 is a widely expressed cation channel of the 'transient receptor potential' (TRP) family that is related to the vanilloid receptor VR1 (TRPV1). It functions as a Ca2+ entry channel and displays remarkable gating promiscuity by responding to both physical stimuli (cell swelling, innoxious heat) and the synthetic ligand 4alphaPDD. 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.

0 (Arachidonic Acids)
0 (Cannabinoid Receptor Modulators)
0 (Cation Transport Proteins)
0 (Endocannabinoids)
0 (Ion Channels)
0 (Polyunsaturated Alkamides)
0 (TRPV Cation Channels)
0 (TRPV4 protein, human)
0 (Trpv4 protein, mouse)
27YG812J1I (Arachidonic Acid)
FC398RK06S (8,11,14-Eicosatrienoic Acid)
SY7Q814VUP (Calcium)
UR5G69TJKH (anandamide)

Date Created: 20030725 Date Completed: 20030813 Latest Revision: 20220330

20250114

10.1038/nature01807

12879072