QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: mol.107.043547v1 73/5/1538    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Clark, M. J. Articles by Traynor, J. R. PubMed PubMed Citation Articles by Clark, M. J. Articles by Traynor, J. R.

Endogenous Regulators of G Protein Signaling Differentially Modulate Full and Partial µ-Opioid Agonists at Adenylyl Cyclase as Predicted by a Collision Coupling Model

Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan (M.J.C., J.R.T.); and Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan (J.J.L.)

Regulator of G protein signaling (RGS) proteins accelerate the endogenous GTPase activity of G_i/o proteins to increase the rate of deactivation of active G-GTP and Gβ signaling molecules. Previous studies have suggested that RGS proteins are more effective on less efficiently coupled systems such as with partial agonist responses. To determine the role of endogenous RGS proteins in functional responses to µ-opioid agonists of different intrinsic efficacy, G_i/o subunits with a mutation at the pertussis toxin (PTX)-sensitive cysteine (C351I) and with or without a mutation at the RGS binding site (G184S) were stably expressed in C6 glioma cells expressing a µ-opioid receptor. Cells were treated overnight with PTX to inactivate endogenous G proteins. Maximal inhibition of forskolin-stimulated adenylyl cyclase by the low-efficacy partial agonists buprenorphine and nalbuphine was increased in cells expressing RGS-insensitive G_o^CIGS, G_i2^CIGS, or G_i3^CIGS compared with their G^CI counterparts, but the RGS-insensitive mutation had little or no effect on the maximal inhibition by the higher efficacy agonists DAMGO and morphine. The potency of all the agonists to inhibit forskolin-stimulated adenylyl cyclase was increased in cells expressing RGS-insensitive G_o^CIGS, G_i2^CIGS, or G_i3^CIGS, regardless of efficacy. These data are comparable with predictions based on a collision coupling model. In this model, the rate of G protein inactivation, which is modulated by RGS proteins, and the rate of G protein activation, which is affected by agonist intrinsic efficacy, determine the maximal agonist response and potency at adenylyl cyclase under steady state conditions.

Address correspondence to: John R. Traynor, 1301 MSRB III/Pharmacology Dept., 1150 W. Medical Center Dr., Ann Arbor, MI 48109-5632. E-mail: jtraynor{at}umich.edu