Bouaboula M, Poinot-Chazel C, Bourrié B, Canat X, Calandra B, Rinaldi-Carmona M, Le Fur G, Casellas P
Sanofi Recherche, Department of Immunopharmacology, Montpellier, France.
Biochem J. 1995 Dec 1;312 ( Pt 2)(Pt 2):637-41. doi: 10.1042/bj3120637.
The G-protein-coupled central cannabinoid receptor (CB1) has been shown to be functionally associated with several biological responses including inhibition of adenylate cyclase, modulation of ion channels and induction of the immediate-early gene Krox-24. Using stably transfected Chinese Hamster Ovary cells expressing human CB1 we show here that cannabinoid treatment induces both phosphorylation and activation of mitogen-activated protein (MAP) kinases, and that these effects are inhibited by SR 141716A, a selective CB1 antagonist. The two p42 and p44 kDa MAP kinases are activated in a time- and dose-dependent manner. The rank order of potency for the activation of MAP kinases with various cannabinoid agonists is CP-55940 > delta 9-tetrahydrocannabinol > WIN 55212.2, in agreement with the pharmacological profile of CB1. The activation of MAP kinases is blocked by pertussis toxin but not by treatment with hydrolysis-resistant cyclic AMP analogues. This suggests that the signal transduction pathway between CB1 and MAP kinases involves a pertussis-toxin-sensitive GTP-binding protein and is independent of cyclic AMP metabolism. This coupling of CB1 subtype and mitogenic signal pathway, also observed in the human astrocytoma cell line U373 MG, may explain the mechanism of action underlying cannabinoid-induced Krox-24 induction.
G蛋白偶联中枢大麻素受体（CB1）已被证明与多种生物学反应在功能上相关，包括抑制腺苷酸环化酶、调节离子通道以及诱导即早基因Krox-24。利用稳定转染表达人CB1的中国仓鼠卵巢细胞，我们在此表明，大麻素处理可诱导丝裂原活化蛋白（MAP）激酶的磷酸化和激活，并且这些效应被选择性CB1拮抗剂SR 141716A抑制。两种分子量分别为42 kDa和44 kDa的MAP激酶以时间和剂量依赖性方式被激活。各种大麻素激动剂激活MAP激酶的效力顺序为CP-55940＞Δ9-四氢大麻酚＞WIN 55212.2，这与CB1的药理学特征一致。百日咳毒素可阻断MAP激酶的激活，但用抗水解的环磷酸腺苷类似物处理则不能。这表明CB1与MAP激酶之间的信号转导途径涉及一种对百日咳毒素敏感的GTP结合蛋白，且独立于环磷酸腺苷代谢。在人星形细胞瘤细胞系U373 MG中也观察到的CB1亚型与促有丝分裂信号途径的这种偶联，可能解释了大麻素诱导Krox-24诱导的作用机制。
