Kam Angel Y F, Chan Anthony S L, Wong Yung H
Department of Biochemistry, the Molecular Neuroscience Center, and the Biotechnology Research Institute, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong.
J Neurochem. 2004 Apr;89(2):391-402. doi: 10.1111/j.1471-4159.2004.02338.x.
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 G beta gamma, 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 PI3K gamma. 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.
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）都是典型的G(i)偶联受体，在调节细胞内事件方面具有共同的信号特征。然而，三种受体对众多信号转导过程的调节存在差异。我们最近证明，刺激δ-阿片受体可以以百日咳毒素敏感的方式上调c-Jun氨基末端激酶（JNK）的活性（Kam等人，2003年；《神经化学杂志》84卷，503 - 513页）。本研究表明，μ-阿片受体在SH-SY5Y细胞和转染的COS-7细胞中均可刺激JNK。通过使用信号中间体的特异性抑制剂和显性负性突变体，阐明了μ-阿片受体刺激JNK的机制。μ-阿片受体对JNK的激活是通过Gβγ、Src激酶、七号染色体失活蛋白（Sos）、Rac和Cdc42介导的。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（PI3K）来激活JNK。渥曼青霉素或PI3Kγ显性负性突变体的共表达可有效抑制μ-阿片受体诱导的JNK激活。与δ-阿片受体一样，κ-阿片受体对JNK的激活以PI3K非依赖的方式发生。这些研究表明，μ-阿片受体利用一种独特的机制来调节JNK。
