The activity of anandamide at vanilloid VR1 receptors requires facilitated transport across the cell membrane and is limited by intracellular metabolism

被引:292
作者
De Petrocellis, L
Bisogno, T
Maccarrone, M
Davis, JB
Finazzi-Agrò, A
Di Marzo, V
机构
[1] CNR, Ist Chim Mol Interesse Biol, Endocannabinoid Grp, I-80072 Arco Felice Napoli, Italy
[2] CNR, Ist Cibernet, I-80072 Arco Felice Napoli, Italy
[3] Univ Roma Tor Vergata, Dept Expt Med & Biochem Sci, Rome, Italy
[4] GlaxoSmithKline, Neurol, Harlow CM19 5AW, Essex, England
关键词
D O I
10.1074/jbc.M008555200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The endogenous ligand of CB1 cannabinoid receptors, anandamide, is also a full agonist at vanilloid VR1 receptors for capsaicin and resiniferatoxin, thereby causing an increase in cytosolic Ca2+ concentration in human VR1-overexpressing (hVR1-HEK) cells. Two selective inhibitors of anandamide facilitated transport into cells, VDM11 and VDM13, and two inhibitors of anandamide enzymatic hydrolysis, phenylmethylsulfonyl fluoride and methylarachidonoyl fluorophosphonate, inhibited and enhanced, respectively, the VR1-mediated effect of anandamide, but not of resiniferatoxin or capsaicin, The nitric oxide donor, sodium nitroprusside, known to stimulate anandamide transport, enhanced anandamide effect on the cytosolic Ca2+ concentration. Accordingly, hVR1-HEK cells contain an anandamide membrane transporter inhibited by VDM11 and VDM13 and activated by sodium nitroprusside, and an anandamide hydrolase activity sensitive to phenylmethylsulfonyl fluoride and methylarachidonoyl fluorophosphonate, and a fatty acid amide hydrolase transcript. These findings suggest the following. (i) Anandamide activates VR1 receptors by acting at an intracellular site. (ii) Degradation by fatty acid amide hydrolase limits anandamide activity on VR1; and (iii) the anandamide membrane transporter inhibitors can be used to distinguish between CB1 or VR1 receptor-mediated actions of anandamide. By contrast, the CB, receptor antagonist SR141716A inhibited also the VR1-mediated effect of anandamide and capsaicin on cytosolic Ca2+ concentration, although at concentrations higher than those required for CB1 antagonism.
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收藏
页码:12856 / 12863
页数:8
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