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• W2113339364 abstract "Agonist-mediated desensitization of the opioid receptors is thought to function as a protective mechanism against sustained opioid signaling and therefore may prevent the development of opioid tolerance. However, the exact molecular mechanism of opioid receptor desensitization remains unresolved because of difficulties in measuring and interpreting receptor desensitization. In the present study, we investigated deltorphin II-mediated rapid desensitization of the human δ opioid receptors (hDOR) by measuring guanosine 5′-<i>O</i>-(3-[³⁵S]thio)-triphosphate binding and inhibition of cAMP accumulation. We developed a mathematical analysis based on the operational model of agonist action (Black et al., 1985) to calculate the proportion of desensitized receptors. This approach permits a correct analysis of the complex process of functional desensitization by taking into account receptor-effector coupling and the time dependence of agonist pretreatment. Finally, we compared hDOR desensitization with receptor phosphorylation at Ser363, the translocation of β-arrestin2, and hDOR internalization. We found that in Chinese hamster ovary cells expressing the hDOR, deltorphin II treatment leads to phosphorylation of Ser363, translocation of β-arrestin2 to the plasma membrane, receptor internalization, and uncoupling from G proteins. It is noteworthy that mutation of the primary phosphorylation site Ser363 to alanine had virtually no effect on agonist-induced β-arrestin2 translocation and receptor internalization yet significantly attenuated receptor desensitization. These results strongly indicate that phosphorylation of Ser363 is the primary mechanism of hDOR desensitization." @default.
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• W2113339364 date "2007-02-22" @default.
• W2113339364 modified "2023-10-04" @default.
• W2113339364 title "Quantitative Evaluation of Human δ Opioid Receptor Desensitization Using the Operational Model of Drug Action" @default.
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• W2113339364 doi "https://doi.org/10.1124/mol.106.030023" @default.
• W2113339364 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/2694736" @default.
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• W2113339364 hasPublicationYear "2007" @default.
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