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• W2028184471 endingPage "815" @default.
• W2028184471 startingPage "809" @default.
• W2028184471 abstract "Chronic exposure of cells to μ-opioid agonists leads to tolerance which can be measured by a reduced ability to activate signaling pathways in the cell. Cell signaling through inhibitory G proteins is negatively regulated by RGS (regulator of G protein signaling) proteins. Here we examine the hypothesis that the GTPase accelerating activity of RGS proteins, by altering the lifetime of Gα and Gβγ, plays a role in the development of cellular tolerance to μ-opioids. C6 glioma cells were stably transfected with μ-opioid receptor and pertussis toxin (PTX)-insensitive Gα_o that was either sensitive or insensitive to endogenous RGS proteins. Cells were treated with PTX to uncouple endogenous Gα proteins followed by exposure to the μ-opioid agonists [d-Ala²,<i>N</i>-Me-Phe⁴,Gly⁵-ol]-enkephalin (DAMGO) or morphine. Receptor desensitization as measured by agonist-stimulated [³⁵S]GTPγS binding and receptor down-regulation as measured by [³H]diprenorphine binding were increased in cells expressing RGS-insensitive Gα_o. Exposure to high concentrations of morphine or the peptidic μ-opioid agonist DAMGO led to a tolerance to inhibit adenylyl cyclase activity in both cell types with a rapid (30 min) and a slower component. Using a submaximal concentration of DAMGO to induce a reduced level of tolerance, a shift in the concentration-effect curve for DAMGO to inhibit adenylyl cyclase activity was seen in the cells expressing RGS-insensitive Gα_o, but not in the cells expressing RGS-sensitive Gα_o, which can be partly explained by an increased supersensitization of the adenylyl cyclase response. The results show that RGS proteins endogenously expressed in C6 cells reduce agonist-induced μ-opioid receptor desensitization, down-regulation, and sensitivity to tolerance to inhibit adenylyl cyclase activity." @default.
• W2028184471 created "2016-06-24" @default.
• W2028184471 creator A5022375777 @default.
• W2028184471 creator A5085381524 @default.
• W2028184471 date "2004-09-21" @default.
• W2028184471 modified "2023-10-17" @default.
• W2028184471 title "Endogenous Regulator of G Protein Signaling Proteins Reduce μ-Opioid Receptor Desensitization and Down-Regulation and Adenylyl Cyclase Tolerance in C6 Cells" @default.
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• W2028184471 doi "https://doi.org/10.1124/jpet.104.074641" @default.
• W2028184471 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/15383633" @default.
• W2028184471 hasPublicationYear "2004" @default.
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