Agonist-directed Interactions with Specific β-Arrestins Determine μ-Opioid Receptor Trafficking, Ubiquitination, and Dephosphorylation
Agonist-directed Interactions with Specific β-Arrestins Determine μ-Opioid Receptor Trafficking, Ubiquitination, and Dephosphorylation
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DOI：
10.1074/jbc.m111.248310
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发表时间：
2011-09-09
影响因子：
4.8
通讯作者：
Bohn, Laura M.
中科院分区：
文献类型：
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作者：
Groer, Chad E.;Schmid, Cullen L.;Bohn, Laura M.
吗啡和其他阿片类药物通过激活mu-阿片受体（MOR）来调节它们的作用，而MOR的调节已被证明对受体的反应性有重要影响。MOR的激活导致受体磷酸化、β -抑制蛋白募集和内化。这个经典的调节过程可能会有所不同，这取决于占据受体的配体。β -拘捕素有两种形式，β -拘捕素1和β -拘捕素2（也分别称为拘捕素2和拘捕素3）；然而，大多数研究都集中在招募β -抑制蛋白2的后果上。在这项研究中，我们通过比较MOR激动剂在缺乏单个或两种β -抑制素表达的细胞中的作用，研究了β -抑制素1和β -抑制素2介导的MOR调节的不同贡献。在这里，我们发现吗啡只招募β -抑制蛋白2，而选择性脑啡肽[D-Ala(2), N-Me-Phe(4), Gly(5)-ol]脑啡肽（DAMGO），招募β -抑制蛋白。我们发现β -抑制素是受体内化所必需的，并且只有β -抑制素2可以挽救吗啡诱导的MOR内化，而β -抑制素可以挽救damgo诱导的MOR内化。随着时间的推移，DAMGO受体的激活促进了MOR泛素化。有趣的是，β -arrestin1被证明对MOR泛素化至关重要，因为在缺乏β -arrestin1或吗啡占据受体时，修饰不会发生。此外，MOR和β -arrestin1之间的选择性相互作用促进受体去磷酸化，这可能在MOR的再敏化中发挥作用，从而促进阿片耐受性的整体发展。
Morphine and other opiates mediate their effects through activation of the mu-opioid receptor (MOR), and regulation of the MOR has been shown to critically affect receptor responsiveness. Activation of the MOR results in receptor phosphorylation, beta-arrestin recruitment, and internalization. This classical regulatory process can differ, depending on the ligand occupying the receptor. There are two forms of beta-arrestin, beta-arrestin1 and beta-arrestin2 (also known as arrestin2 and arrestin3, respectively); however, most studies have focused on the consequences of recruiting beta-arrestin2 specifically. In this study, we examine the different contributions of beta-arrestin1- and beta-arrestin2-mediated regulation of the MOR by comparing MOR agonists in cells that lack expression of individual or both beta-arrestins. Here we show that morphine only recruits beta-arrestin2, whereas the MOR-selective enkephalin [D-Ala(2), N-Me-Phe(4), Gly(5)-ol] enkephalin (DAMGO), recruits either beta-arrestin. We show that beta-arrestins are required for receptor internalization and that only beta-arrestin2 can rescue morphine-induced MOR internalization, whereas either beta-arrestin can rescue DAMGO-induced MOR internalization. DAMGO activation of the receptor promotes MOR ubiquitination over time. Interestingly, beta-arrestin1 proves to be critical for MOR ubiquitination as modification does not occur in the absence of beta-arrestin1 nor when morphine occupies the receptor. Moreover, the selective interactions between the MOR and beta-arrestin1 facilitate receptor dephosphorylation, which may play a role in the resensitization of the MOR and thereby contribute to overall development of opioid tolerance.