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CELLULAR AND MOLECULAR

Endogenous Regulator of G Protein Signaling Proteins Suppress Go-Dependent, µ-Opioid Agonist-Mediated Adenylyl Cyclase Supersensitization

Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan

Chronic µ-opioid agonist treatment leads to dependence with withdrawal on removal of agonist. At the cellular level withdrawal is accompanied by a supersensitization of adenylyl cyclase, an effect that requires inhibitory G proteins. Inhibitory G protein action is modulated by regulator of G protein signaling (RGS) proteins that act as GTPase activating proteins and reduce the lifetime of G-GTP. In this article, we use C6 glioma cells expressing the rat µ-opioid receptor (C6µ) to examine the hypothesis that Go alone can mediate µ-opioid agonist induced adenylyl cyclase supersensitivity and that endogenous RGS proteins serve to limit the extent of this supersensitization. C6µ cells were stably transfected with pertussis toxin (PTX)-insensitive Go that was either sensitive or insensitive to endogenous RGS proteins. Cells were treated with PTX to uncouple endogenous G proteins followed by exposure to the µ-opioid agonists [D-Ala²,N-Me-Phe⁴,Gly⁵-ol]-enkephalin or morphine. Supersensitization was observed in cells expressing wild-type G, but this was lost on PTX treatment. In cells expressing PTX-insensitive Go supersensitization was recovered, confirming that Go alone can support supersensitization. In cells expressing the RGS-insensitive mutant Go, there was a greater degree of supersensitization and the concentration of µ-agonist needed to achieve half-maximal supersensitization was reduced by 10-fold. The amount of supersensitization seen did not directly relate to the degree of acute inhibition of adenylyl cyclase. These results demonstrate a role for Go in adenylyl cyclase supersensitization after µ-agonist exposure and show that this action is modulated by endogenous RGS proteins.

Address correspondence to: Dr. John R. Traynor, Department of Pharmacology, University of Michigan Medical Center, Ann Arbor, MI 48109-0632. E-mail: jtraynor{at}umich.edu

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