Role for G protein-coupled receptor kinase in agonist-specific regulation of μ-opioid receptor responsiveness
Role for G protein-coupled receptor kinase in agonist-specific regulation of μ-opioid receptor responsiveness
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DOI：
10.1073/pnas.95.12.7157
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发表时间：
1998-06-09
影响因子：
11.1
通讯作者：
Caron, MG
中科院分区：
文献类型：
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作者：
Zhang, J;Ferguson, SSG;Caron, MG
G蛋白偶联的mu-阿片受体（mu OR）介导内源性阿片肽以及结构不同的阿片生物碱吗啡和艾托啡的生理作用。mu OR信号的一个有趣的特征是不同受体在不同激动剂激活后的不同转运和脱敏特性，这被认为是与阿片耐受性相关的可能机制。在这里，我们报道了不同的阿片受体激动剂调节mu OR内化和脱敏的能力与它们促进G蛋白偶联受体激酶（GRK）依赖性的mu OR磷酸化的能力有关。虽然乙托啡和吗啡都能有效地激活mu OR，但只有乙托啡能引起强大的mu OR磷酸化，随后是β -抑制素和动力蛋白依赖受体内化的质膜易位。相反，与无法引起mu OR内化相对应，吗啡既不能引起mu OR磷酸化，也不能刺激β -抑制蛋白易位。然而，在GRK2过表达的情况下，吗啡获得了诱导mu OR磷酸化的能力，并伴有β -抑制素易位和受体隔离的拯救。此外，GRK2的过表达也会导致吗啡介导的腺苷酸环化酶抑制的减弱。这些发现表明，不同的阿片受体激动剂促进GRK对mu OR磷酸化的能力存在显著差异。这些差异可能提供了阿片激动剂不同镇痛特性的分子基础，并有助于不同阿片激动剂诱导药物耐受的不同能力。
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.