期刊
NEUROPHARMACOLOGY
卷 39, 期 10, 页码 1707-1719出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/S0028-3908(99)00243-9
关键词
phosphorylation; opioids; concanavalin A; MAP kinase; receptor internalization
资金
- NIDA NIH HHS [DA00017, T32DA07254] Funding Source: Medline
- NATIONAL INSTITUTE ON DRUG ABUSE [T32DA007254] Funding Source: NIH RePORTER
Agonist-promoted internalization (endocytosis) of G-protein-coupled receptors (GPCRs), including all three opioid receptor types (mu, delta and kappa), has been shown to occur via the clathrin endosomal pathway in response to receptor phosphorylation and the actions of the proteins, beta-arrestin and dynamin. Many members of the GPCR family stimulate mitogen-activated protein kinases (MAPK or ERK) activity and, in several cases, it appears that MAPK activation is dependent on receptor internalization. We have reinvestigated the question of whether internalization is obligatory for MAPK activation by opioid receptors, using cell lines expressing the cloned mu or delta receptor. Morphine, which is known to activate both mu and delta receptors, does not induce their rapid internalization into clathrin-coated endosomes. However, morphine produced a robust stimulation of MAPK in both cell lines, as demonstrated by the appearance of phosphorylated MAPK. Moreover, pre-exposure of cells to the internalization inhibitors, concanavalin A or hypertonic sucrose, totally blocked DAMGO (mu-selective agonist) and DTLET (delta-selective agonist)-mediated receptor internalization, yet neither treatment affected MAPK phosphorylation induced by these peptides. Our results provide evidence that receptor internalization is not an obligatory requirement for MAPK activation by mu and delta opioid receptors. Hypotheses are presented to explain the seemingly contradictory results obtained from different laboratories. (C) 2000 Elsevier Science Ltd. All rights reserved.
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