Anandamide and arachidonic acid use epoxyeicosatrienoic acids to activate TRPV4 channels

Abstract

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.

The TRPV3 mutation associated with the hairless phenotype in rodents is constitutively active

“…TRPV4 is activated by osmolarity changes [10,11], by the epoxygenase products of arachidonic acid [12], and by bisandrographolide from the medicinal plant, Andrographis Paniculata [13]. TRPV3 is activated by a number of plant extracts, such as camphor [8], carvacrol (from oregano) eugenol (from clove), and thymol (from thyme) [14].…”

Inhibition of soluble epoxide hydrolase reduces LPS-induced thermal hyperalgesia and mechanical allodynia in a rat model of inflammatory pain

“…This difference could be explained by the fact that we used a mixture of four regioisomers of EETs, one or more of which could have exerted a relatively greater pro-nociceptive versus antinociceptive action. Potential pro-nociceptive properties of EETs include activation of the heatsensitive, mechanosensitive and osmosensitive TRPV4 receptor Vriens et al, 2005;Vriens et al, 2004;Watanabe et al, 2003), or in the case of 5,6-EET, conversion to prostaglandins by COX (Carroll et al, 1993). We are not certain why EETs were antihyperalgesic in LPS-treated rats and pro-nociceptive in LPS-naïve animals.…”

Cannabinoids, the Heart of the Matter

“…TRPV1 ion channels have important functions as cellular sensors, and are involved in nociception, taste perception, thermosensation, mechano‐ and osmolarity sensing, and regulation of signal transmission 15, 55, 56. In addition to ECS and physicochemical activators,15, 33, 55, 56, 57, 58 TRPV1 is activated by tetrahydrocannabinol, cannabinol, cannabigerol and some propyl homologs of THC and cannabigerol 59, 60, 61, 62, 63, 64, 65, 66, 67. Cannabichromene (CBC), cannabidiol, and cannabinol are strong TRPA1 agonists and desensitizers, and THCV (from a botanical extract) is a potent regulator of TRPA1 62…”