Hypersensitization of the orexin 1 receptor by the CB1 receptor -: Evidence for cross-talk blocked by the specific CB1 antagonist, SR141716
Hypersensitization of the orexin 1 receptor by the CB1 receptor -: Evidence for cross-talk blocked by the specific CB1 antagonist, SR141716
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DOI：
10.1074/jbc.m212369200
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发表时间：
2003-06-27
影响因子：
4.8
通讯作者：
Casellas, P
中科院分区：
文献类型：
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作者：
Hilairet, S;Bouaboula, M;Casellas, P
在本研究中，我们观察到大麻素受体CB 1和食欲素1受体（OX 1 R）使用异源系统之间的串扰的证据。当这两种受体共表达时，我们观察到食欲素A激活促分裂原活化蛋白激酶途径的效力的主要CB 1依赖性增强;剂量响应曲线表明食欲素介导的促分裂原活化蛋白激酶激活的效力增加了100倍。这种效应需要功能性CB 1受体，如特异性CB 1拮抗剂N-（哌啶子基-1-基）-5-（4-氯苯基）-1-（2，4-二氯苯基）-4-甲基-吡唑-3-甲酰胺（SR 141716）阻断食欲素反应所证明，但百日咳毒素也阻断食欲素反应，表明这种增强作用是G（i）介导的。与OX 1 R相反，CB 1的直接激活效力不受与OX 1 R共表达的影响。此外，电子显微镜实验显示，CB 1和OX 1 R在质膜水平上紧密并列;它们足够接近以形成异源寡聚体。总而言之，我们的数据第一次提供证据表明CB 1能够增强食欲受体。考虑到SR 141716的抗肥胖作用，这些结果为理解该分子通过CB 1与其他参与食欲控制的受体之间的功能相互作用预防体重增加的机制开辟了新途径。
In the present study, we observed evidence of crosstalk between the cannabinoid receptor CB1 and the orexin 1 receptor (OX1R) using a heterologous system. When the two receptors are co-expressed, we observed a major CB1-dependent enhancement of the orexin A potency to activate the mitogen-activated protein kinase pathway; dose-responses curves indicated a 100-fold increase in the potency of orexin-mediated mitogen-activated protein kinase activation. This effect required a functional CB1 receptor as evidenced by the blockade of the orexin response by the specific CB1 antagonist, N-(piperidino-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-pyrazole-3-carboxamide (SR141716), but also by pertussis toxin, suggesting that this potentiation is G(i)-mediated. In contrast to OX1R, the potency of direct activation of CB1 was not affected by co-expression with OX1R. In addition, electron microscopy experiments revealed that CB1 and OX1R are closely apposed at the plasma membrane level; they are close enough to form hetero-oligomers. Altogether, for the first time our data provide evidence that CB1 is able to potentiate an orexigenic receptor. Considering the anti-obesity effect of SR141716, these results open new avenues to understand the mechanism by which the molecule may prevent weight gain through functional interaction between CB1 and other receptors involved in the control of appetite.