Endogenous regulator of g protein signaling proteins reduce {mu}-opioid receptor desensitization and down-regulation and adenylyl cyclase tolerance in C6 cells

The Journal of Pharmacology and Experimental Therapeutics
M J Clark, John R Traynor

Abstract

Chronic exposure of cells to mu-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 Galpha and Gbetagamma, plays a role in the development of cellular tolerance to mu-opioids. C6 glioma cells were stably transfected with mu-opioid receptor and pertussis toxin (PTX)-insensitive Galpha(o) that was either sensitive or insensitive to endogenous RGS proteins. Cells were treated with PTX to uncouple endogenous Galpha proteins followed by exposure to the mu-opioid agonists [d-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO) or morphine. Receptor desensitization as measured by agonist-stimulated [(35)S]GTPgammaS binding and receptor down-regulation as measured by [(3)H]diprenorphine binding were increased in cells expressing RGS-insensitive Galpha(o). Exposure to high concentrations of morphine or the peptidic mu-opioid agonist DAMGO led to a tolerance to inhibit adenylyl cyclase activity in both cell types with a rapid (30 min) and a s...Continue Reading

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Mar 12, 2004·The Journal of Pharmacology and Experimental Therapeutics·Mary J ClarkJohn R Traynor

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Citations

Jul 7, 2005·Supportive Care in Cancer : Official Journal of the Multinational Association of Supportive Care in Cancer·Mellar P DavisRuth Lagman
Sep 1, 2006·Molecular and Cellular Biology·Xinyan HuangRichard R Neubig
Jun 5, 2008·Biochemistry and Cell Biology = Biochimie Et Biologie Cellulaire·Katarzyna GachAnna Janecka
Sep 16, 2006·Peptides·Richard J Bodnar, Gad E Klein
Jun 1, 2020·Molecular Pharmacology·Farhana SaklothVenetia Zachariou

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