Zhang J, Ferguson S S, Barak L S, Bodduluri S R, Laporte S A, Law P Y, Caron M G
Howard Hughes Medical Institute Laboratories and Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA.
Proc Natl Acad Sci U S A. 1998 Jun 9;95(12):7157-62. doi: 10.1073/pnas.95.12.7157.
The G protein-coupled mu-opioid receptor (mu OR) mediates the physiological effects of endogenous opioid peptides as well as the structurally distinct opioid alkaloids morphine and etorphine. An intriguing feature of mu OR signaling is the differential receptor trafficking and desensitization properties following activation by distinct agonists, which have been proposed as possible mechanisms related to opioid tolerance. Here we report that the ability of distinct opioid agonists to differentially regulate mu OR internalization and desensitization is related to their ability to promote G protein-coupled receptor kinase (GRK)-dependent phosphorylation of the mu OR. Although both etorphine and morphine effectively activate the mu OR, only etorphine elicits robust mu OR phosphorylation followed by plasma membrane translocation of beta-arrestin and dynamin-dependent receptor internalization. In contrast, corresponding to its inability to cause mu OR internalization, morphine is unable to either elicit mu OR phosphorylation or stimulate beta-arrestin translocation. However, upon the overexpression of GRK2, morphine gains the capacity to induce mu OR phosphorylation, accompanied by the rescue of beta-arrestin translocation and receptor sequestration. Moreover, overexpression of GRK2 also leads to an attenuation of morphine-mediated inhibition of adenylyl cyclase. These findings point to the existence of marked differences in the ability of different opioid agonists to promote mu OR phosphorylation by GRK. These differences may provide the molecular basis underlying the different analgesic properties of opioid agonists and contribute to the distinct ability of various opioids to induce drug tolerance.
G蛋白偶联的μ-阿片受体（μOR）介导内源性阿片肽以及结构不同的阿片生物碱吗啡和埃托啡的生理效应。μOR信号传导的一个有趣特征是，在被不同激动剂激活后，受体的转运和脱敏特性存在差异，这被认为是与阿片类药物耐受性相关的可能机制。在此我们报告，不同阿片类激动剂对μOR内化和脱敏的差异调节能力与其促进μOR的G蛋白偶联受体激酶（GRK）依赖性磷酸化的能力有关。虽然埃托啡和吗啡都能有效激活μOR，但只有埃托啡能引发强烈的μOR磷酸化，随后β-抑制蛋白发生质膜转位以及动力蛋白依赖性受体内化。相反，由于吗啡无法导致μOR内化，它既不能引发μOR磷酸化，也不能刺激β-抑制蛋白转位。然而，当GRK2过表达时，吗啡获得了诱导μOR磷酸化的能力，同时β-抑制蛋白转位和受体隔离得以恢复。此外，GRK2的过表达还导致吗啡介导的腺苷酸环化酶抑制作用减弱。这些发现表明，不同阿片类激动剂通过GRK促进μOR磷酸化的能力存在显著差异。这些差异可能为阿片类激动剂不同的镇痛特性提供分子基础，并有助于各种阿片类药物诱导药物耐受性的不同能力。
