PT  - JOURNAL ARTICLE
AU  - Ann E. Remmers
AU  - Mary J. Clark
AU  - Xiang Yang Liu
AU  - Fedor Medzihradsky
TI  - <em>Delta</em> Opioid Receptor Down-Regulation Is Independent of Functional G Protein yet Is Dependent on Agonist Efficacy
DP  - 1998 Nov 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 625--632
VI  - 287
IP  - 2
4099  - http://jpet.aspetjournals.org/content/287/2/625.short
4100  - http://jpet.aspetjournals.org/content/287/2/625.full
SO  - J Pharmacol Exp Ther1998 Nov 01; 287
AB  - Chronic treatment of C6 glioma cells stably expressing the ratdelta opioid receptor (C6δ) with full agonists resulted in receptor down-regulation. Chronic [d-Ser2,l-Leu5]enkephalyl-Thr treatment caused a decrease in cell surface as well as a decrease in agonist-stimulated [35S]guanosine-5′-O-(3-thio)triphosphate binding. Treatment with full agonists for 12 hr resulted in a 90% decrease in receptor number that was paralleled by a decrease in the ability of agonist to stimulate [35S]guanosine-5′-O-(3-thio)triphosphate binding and inhibit forskolin-stimulated adenylyl cyclase. Of the remaining receptors, a smaller fraction of receptors (41 ± 4 vs.56 ± 4% in control) exhibited high affinity for agonist as compared to receptors in control membranes. Elimination of functional guanosine triphosphate binding protein (G protein) by Pertussis toxin pretreatment did not alter the ability of agonist to down regulate receptor. We hypothesized that agonist affinity (not efficacy) would be a predictor of an agonist’s ability to down-regulate receptor. However, we found that only full agonists were able to down-regulate receptor number, G protein activation and adenylyl cyclase inhibition. Chronic exposure to partial agonist 7-spiroindinooxymorphone, which has a very high affinity for the receptor, as well as morphine, did not cause receptor down-regulation. Taken together, these results suggest that full agonists alter receptor conformation such that the altered conformation is recognized by G protein as well as proteins involved in receptor down-regulation. In addition, down-regulation is independent of agonist-mediated G protein activation and subsequent down-stream signaling. The American Society for Pharmacology and Experimental Therapeutics