Direct inhibition by cannabinoids of human 5-HT3A receptors:: probable involvement of an allosteric modulatory site

被引:158
作者
Barann, M
Molderings, G
Brüss, M
Bönisch, H
Urban, BW
Göthert, M
机构
[1] Univ Bonn, Inst Pharmakol & Toxikol, D-53113 Bonn, Germany
[2] Univ Kliniken Bonn, Klin Anasthesiol & Spezielle Intens Med, D-53105 Bonn, Germany
关键词
allosteric site; anandamide; cannabinoid; CB1; receptor; excised patch; 5-HT3; voltage-clamp;
D O I
10.1038/sj.bjp.0704829
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
1 Excised outside-out patches from HEK293 cells stably transfected with the human (h) 5-HT3A receptor cDNA were used to determine the effects of cannabinoid receptor ligands on the 5-HT-induced current using the patch clamp technique. In addition, binding studies with radioligands for 5-HT3 as well as for cannabinoid CB1 and CB2 receptors were carried out. 2 The 5-HT-induced current was inhibited by the following cannabinoid receptor agonists (at decreasing order of potency): Delta(9)-THC, WIN55,212-2, anandamide, JWH-015 and CP55940. The WIN55,212-2-induced inhibition was not altered by SR141716A, a CB1 receptor antagonist. WIN55,212-3, an enantiomer of WIN55,212-2, did not affect the 5-HT-induced current. 3 WIN55,212-2 did not change the EC50 value of 5-HT in stimulating current, but reduced the maximum effect. 4 The CB, receptor ligand [H-3]-SR141716A and the CB1/CB2 receptor ligand [H-3]-CP55940 did not specifically bind to parental HEK293 cells. In competition experiments on membranes of HEK293 cells transfected with the h5-HT3A receptor cDNA, WIN55,212-2, CP55940, anandamide and SR141716A did not affect [H-3]-GR65630 binding, but 5-HT caused a concentration dependent-inhibition. 5 In conclusion, cannabinoids stereoselectively inhibit currents through recombinant h5-HT3A receptors independently of cannabinoid receptors. Probably the cannabinoids act allosterically at a modulatory site of the h5-HT3A receptor. Thus the functional state of the receptor can be controlled by the endogenous ligand anandamide. This site is a potential target for new analgesic and antiemetic drugs.
引用
收藏
页码:589 / 596
页数:8
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