PT  - JOURNAL ARTICLE
AU  - Graciela Piñeyro
AU  - Mounia Azzi
AU  - André deLéan
AU  - Peter W. Schiller
AU  - Michel Bouvier
TI  - Reciprocal Regulation of Agonist and Inverse Agonist Signaling Efficacy upon Short-Term Treatment of the Human δ-Opioid Receptor with an Inverse Agonist
AID  - 10.1124/mol.104.004549
DP  - 2005 Jan 01
TA  - Molecular Pharmacology
PG  - 336--348
VI  - 67
IP  - 1
4099  - http://molpharm.aspetjournals.org/content/67/1/336.short
4100  - http://molpharm.aspetjournals.org/content/67/1/336.full
SO  - Mol Pharmacol2005 Jan 01; 67
AB  - Rapid regulation of receptor signaling by agonist ligands is widely accepted, whereas short-term adaptation to inverse agonists has been little documented. In the present study, guanosine 5′-O-(3-[35S]thio)triphosphate ([35S]GTPγS) binding and cAMP accumulation assays were used to assess the consequences of 30-min exposure to the inverse agonist N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH (ICI174864) (1 μM) on δ-opioid receptor signaling efficacy. ICI174864 pretreatment increased maximal effect (Emax) for the partial agonist Tyr-1,2,3,4-tetrahydroisoquinoline-Phe-Phe-OH (TIPP) at the two levels of the signaling cascade, whereas Emax values for more efficacious agonists like (+)-4-[(αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC-80) and bremazocine were increased in [35S]GTPγS binding but not in cAMP accumulation assays. Pre-exposure to ICI174864 also induced a shift to the left in dose-response curves for bremazocine and TIPP. On the other hand, Emax for the inverse agonist H-Tyr-TicΨ[CH2NH]Cha-Phe-OH was reduced in both assays, but no changes in potency were observed. For the weaker inverse agonist naloxone, Emax in [35S]GTPγS binding was drastically modified because the drug turned from inverse agonist to agonist after ICI174864 pretreatment. Likewise, ICI174864 turned from inverse agonist to agonist when tested in cAMP accumulation assays. In both cases, inversion of efficacy was concomitant with marked increase in potency for agonist effects. Together with functional changes, short-term treatment with ICI174864 reduced basal receptor phosphorylation and increased immunoreactivity for Gαi3 in membrane preparations. Functional consequences of ICI174864 pretreatment were simulated in the cubic ternary complex model by increasing receptor/G protein coupling or G protein amount available for interaction with the receptor. Taken together, these data show that inverse agonists may induce rapid regulation in receptor signaling efficacy.