期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 105, 期 27, 页码 9421-9426出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0802253105
关键词
lipid raft; opioid
资金
- NIDA NIH HHS [R01 DA016674, K05-DA70544, R01 DA000564, DA000564, K05 DA000513, DA011806, DA016674, K05-DA00513, R56 DA000564, R01 DA007339, P50 DA011806, DA007339] Funding Source: Medline
The basis for agonist-selective signaling was investigated by using the mu-opioid receptor (MOR) as a model. In the absence of agonist, MOR located within the lipid raft domains, whereas etorphine, but not morphine, induced the translocation of MOR from lipid raft to nonraft domains, similar to the action of methyl-beta-cyclodextrin. The etorphine-induced MOR translocation required the dissociation of the receptor from G alpha i2 first and then the binding of beta-arrestin. In contrast, the low affinity of the morphine-MOR complex for beta-arrestin and the rebinding of G alpha i2 after GTP hydrolysis retained the complex within the lipid raft domains. Disruption of the MOR-G alpha i2 interaction, either by deleting the (RRITR280)-R-276 sequence of MOR or knocking down the level of G alpha i2, resulted in the translocation of MOR to the nonraft domains. In addition, lipid raft location of MOR was critical for G protein-dependent signaling, such as etorphine- and morphine-mediated inhibition of adenylyl cyclase activity and morphine-induced ERK phosphorylation, whereas beta-arrestin-dependent, etorphine-induced ERK phosphorylation required MOR to translocate into the nonraft domains. Thus, agonist-selective signaling is regulated by the location of MOR, which is determined by interactions of MOR with G proteins and beta-arrestin.
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