Opioid agonists have different efficacy profiles for G protein activation, rapid desensitization, and endocytosis of Mu-opioid receptors

Stephanie L. Borgland, Mark Connor*, Peregrine B. Osborne, John B. Furness, MacDonald J. Christie

*Corresponding author for this work

Research output: Contribution to journalArticle

136 Citations (Scopus)

Abstract

The differential ability of various μ-opioid receptor (MOP) agonists to induce rapid receptor desensitization and endocytosis of MOP could arise simply from differences in their efficacy to activate G proteins or, alternatively, be due to differential capacity for activation of other signaling processes. We used AtT20 cells stably expressing a low density of FLAG-tagged MOP to compare the efficacies of a range of agonists to 1) activate G proteins using inhibition of calcium channel currents (ICa) as a reporter before and after inactivation of a fraction of receptors by β-chlornaltrexamine, 2) produce rapid, homologous desensitization of ICa inhibition, and 3) internalize receptors. Relative efficacies determined for G protein coupling were [Tyr-D-Ala-Gly-MePhe-Glyol]enkephalin (DAMGO) (1) ≥ methadone (0.98) > morphine (0.58) > pentazocine (0.15). The same rank order of efficacies for rapid desensitization of MOP was observed, but greater concentrations of agonist were required than for G protein activation. By contrast, relative efficacies for promoting endocytosis of MOP were DAMGO (1) > methadone (0.59) ≫ morphine (0.07) ≥ pentazocine (0.03). These results indicate that the efficacy of opioids to produce activation of G proteins and rapid desensitization is distinct from their capacity to internalize μ-opioid receptors but that, contrary to some previous reports, morphine can produce rapid, homologous desensitization of MOP.

Original languageEnglish
Pages (from-to)18776-18784
Number of pages9
JournalJournal of Biological Chemistry
Volume278
Issue number21
DOIs
Publication statusPublished - 23 May 2003
Externally publishedYes

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