Signaling pathway associated with stimulation of CB2 peripheral cannabinoid receptor - Involvement of both mitogen-activated protein kinase and induction of Krox-24 expression
Signaling pathway associated with stimulation of CB2 peripheral cannabinoid receptor - Involvement of both mitogen-activated protein kinase and induction of Krox-24 expression
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DOI：
10.1111/j.1432-1033.1996.0704p.x
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发表时间：
1996-05-01
期刊：
影响因子：
--
通讯作者：
Casellas, P
中科院分区：
文献类型：
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作者：
Bouaboula, M;PoinotChazel, C;Casellas, P
以其精神活性作用而闻名的大麻素也具有免疫调节特性。最近分离和克隆的G-蛋白偶联外周大麻素受体（CB 2），主要在免疫组织中表达，提供了分子工具，以确定大麻素化合物如何介导免疫调节。在这里，我们研究了CB 2的信号转导特性，使用稳定转染的中国仓鼠卵巢细胞表达人CB 2。首先，我们发现大麻素激动剂的刺激以时间和剂量依赖的方式激活丝裂原活化蛋白（MAP）激酶。大麻素激动剂的MAP激酶激活效力的等级顺序与它们的结合能力很好地相关。其次，我们证明了在MAP激酶激活后，大麻素诱导了生长相关基因Krox-24（也称为NGFI-A，zif/268和p53 -1）的表达。百日咳毒素完全阻止MAP激酶激活和Krox-24诱导，即使在这些反应似乎是依赖于特定的蛋白激酶C亚型和腺苷酸环化酶的抑制独立。在人早幼粒细胞HL 60中也观察到CB 2与促有丝分裂途径和Krox-24表达调节的类似偶联。总之，这些研究结果提供了证据CB 2受体在MAP激酶网络介导的基因诱导中的功能作用。
Cannabinoids, known for their psychoactive effects, also possess immunomodulatory properties. The recent isolation and cloning of the G-protein-coupled peripheral cannabinoid receptor (CB2), mainly expressed in immune tissues, have provided molecular tools to determine how cannabinoid compounds may mediate immunomodulation. We here investigated the CB2 signaling properties using stably transfected Chinese hamster ovary cells expressing human CB2. First, we showed that stimulation by a cannabinoid agonist activated mitogen-activated protein (MAP) kinase in time- and dose-dependent manners. The rank order of potency for MAP kinase activation of cannabinoid agonists correlated well with their binding capacities. Second, we demonstrated that, following MAP kinase activation, cannabinoids induced the expression of the growth-related gene Krox-24, also known as NGFI-A, zif/268, and egr-1. Pertussis toxin completely prevented both MAP kinase activation and Krox-24 induction, even mon these responses appeared to be dependent of specific proteine kinase C isoforms and independent of inhibition of adenylyl cyclase. A similar coupling of CB2 to a mitogenic pathway and to the regulation of Krox-24 expression was also observed in human promyelocytic cells HL60. Taken together, these findings provide evidence for a functional role of the CB2 receptor in gene induction mediated by the MAP kinase network.