Anandamide and arachidonic acid use epoxyeicosatrienoic acids to activate TRPV4 channels
Anandamide and arachidonic acid use epoxyeicosatrienoic acids to activate TRPV4 channels
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DOI：
10.1038/nature01807
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发表时间：
2003-07-24
期刊：
影响因子：
64.8
通讯作者：
Nilius, B
中科院分区：
文献类型：
--
作者：
Watanabe, H;Vriens, J;Nilius, B
TRPV 4是与香草酸受体VR 1（TRPV 1）相关的“瞬时受体电位”（TRP）家族（1）的一种广泛表达的阳离子通道。它作为Ca 2+进入通道发挥作用（2），并通过响应物理刺激（细胞肿胀，无害热（2-7））和合成配体4 α PDD（8）显示出显著的门控混杂性。该通道的内源性配体尚未确定。在这里，我们表明，内源性大麻素anandamide和其代谢产物花生四烯酸激活TRPV 4的间接方式涉及细胞色素P450环氧酶依赖的形成epoxyeicosatrienoic酸。应用亚微摩尔浓度的5 '，6'-环氧二十碳三烯酸以膜界定的方式激活TRPV 4，并导致Ca 2+通过血管内皮细胞中的TRPV 4样通道内流。因此，血管内皮细胞中TRPV 4的激活可能有助于内源性大麻素及其P450环氧酶依赖性代谢物对血管张力的舒张作用（9-12）。
TRPV4 is a widely expressed cation channel of the 'transient receptor potential' (TRP) family(1) that is related to the vanilloid receptor VR1 (TRPV1). It functions as a Ca2+ entry channel(2) and displays remarkable gating promiscuity by responding to both physical stimuli (cell swelling, innoxious heat(2-7)) and the synthetic ligand 4alphaPDD(8). 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(9-12).