Phosphatidylinositol-3 kinase is distinctively required for μ-, but not κ-opioid receptor-induced activation of c-Jun N-terminal kinase
Phosphatidylinositol-3 kinase is distinctively required for μ-, but not κ-opioid receptor-induced activation of c-Jun N-terminal kinase
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DOI：
10.1111/j.1471-4159.2004.02338.x
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发表时间：
2004-04-01
影响因子：
4.7
通讯作者：
Wong, YH
中科院分区：
文献类型：
--
作者：
Kam, AYF;Chan, ASL;Wong, YH
阿片受体是麻醉性镇痛药的治疗靶点。所有三种类型的阿片受体（μ、δ和κ）都是原型G（i）偶联受体，在其调节细胞内事件中具有共同的信号传导特征。然而，许多信号传导过程由三种受体差异调节。我们最近已经证明，δ-阿片受体的刺激可以以百日咳毒素敏感的方式上调c-Jun N-末端激酶（JNK）的活性（Kam等人，2003; J. Neurochem. 84，503-513）。本研究发现μ阿片受体在SH-SY 5 Y细胞和转染的COS-7细胞中均能激活JNK。μ-阿片受体刺激JNK的机制与使用特定的抑制剂和信号传导中间体的显性负突变体描绘。μ-阿片受体对JNK的激活通过Gbetagamma、Src激酶、Sos、Rac和Cdc 42介导。有趣的是，与δ-阿片受体不同，μ-阿片受体需要磷脂酰肌醇-3激酶（PI 3 K）来激活JNK。μ-阿片受体诱导的JNK激活被渥曼青霉素或PI 3 K γ显性负突变体的共表达有效抑制。与δ-阿片受体一样，κ-阿片受体对JNK的激活以PI 3 K非依赖性方式发生。这些研究表明，μ阿片受体利用独特的机制来调节JNK。
Opioid receptors are the therapeutic targets of narcotic analgesics. All three types of opioid receptors (mu, delta and kappa) are prototypical G(i)-coupled receptors with common signaling characteristics in their regulation of intracellular events. Nevertheless, numerous signaling processes are differentially regulated by the three receptors. We have recently demonstrated that stimulation of delta-opioid receptor can up-regulate the activity of the c-Jun N-terminal kinase (JNK) in a pertussis toxin-sensitive manner (Kam et al. 2003; J. Neurochem. 84, 503-513). The present study revealed that the mu-opioid receptor could stimulate JNK in both SH-SY5Y cells and transfected COS-7 cells. The mechanism by which the mu-opioid receptor stimulated JNK was delineated with the use of specific inhibitors and dominant-negative mutants of signaling intermediates. Activation of JNK by the mu-opioid receptor was mediated through Gbetagamma, Src kinase, son-of-sevenless (Sos), Rac and Cdc42. Interestingly, unlike the delta-opioid receptors, the mu-opioid receptor required phosphatidylinositol-3 kinase (PI3K) to activate JNK. The mu-opioid receptor-induced JNK activation was effectively inhibited by wortmannin or the coexpression of a dominant negative mutant of PI3Kgamma. Like the delta-opioid receptor, activation of JNK by the kappa-opioid receptor occurred in a PI3K-independent manner. These studies revealed that the mu-opioid receptor utilize a distinct mechanism to regulate JNK.