Involvement of PKCalpha and G-protein-coupled receptor kinase 2 in agonist-selective desensitization of micro-opioid receptors in mature brain neurons

C.P Bailey, S Oldfield, F.J Llorente, C.J Caunt, A.G Teschemacher, L Roberts, C.A McArdle, F.L Smith, W.L Dewey, E Kelly, G Henderson

Research output: Contribution to journalArticle (Academic Journal)peer-review

67 Citations (Scopus)

Abstract

Background and purpose:  The ability of an agonist to induce desensitization of the µ-opioid receptor (MOR) depends upon the agonist used. Furthermore, previous data suggest that the intracellular mechanisms underlying desensitization may be agonist-specific. We investigated the mechanisms underlying MOR desensitization, in adult mammalian neurons, caused by morphine (a partial agonist in this system) and DAMGO (a high-efficacy agonist). Experimental approach:  MOR function was measured in locus coeruleus neurons, by using whole-cell patch-clamp electrophysiology, in rat and mouse brain slices (both wild-type and protein kinase C (PKC)α knockout mice). Specific isoforms of PKC were inhibited by using inhibitors of the receptors for activated C-kinase (RACK), and in vivo viral-mediated gene-transfer was used to transfect neurons with dominant negative mutants (DNMs) of specific G-protein-coupled receptor kinases (GRKs). Key results:  Morphine-induced desensitization was attenuated by using RACK inhibitors that inhibit PKCα, but not by other isoform-specific inhibitors. Further, the PKC component of morphine-induced desensitization was absent in locus coeruleus neurons from PKCα knockout mice. The PKC-enhanced morphine-induced desensitization was not affected by over-expression of a GRK2 dominant negative mutant (GRK2 DNM). In contrast, DAMGO-induced MOR desensitization was independent of PKC activity but was reduced by over-expression of the GRK2 DNM but not by that of a GRK6 DNM. Conclusions and implications:  In mature mammalian neurons, different MOR agonists can induce MOR desensitization by different mechanisms, morphine by a PKCα-mediated, heterologous mechanism and DAMGO by a GRK-mediated, homologous mechanism. These data represent functional selectivity at the level of receptor desensitization.
Translated title of the contributionInvolvement of PKCalpha and G-protein-coupled receptor kinase 2 in agonist-selective desensitization of micro-opioid receptors in mature brain neurons
Original languageEnglish
Pages (from-to)157 - 164
Number of pages8
JournalBritish Journal of Pharmacology
Volume158
Issue number1
DOIs
Publication statusPublished - Sep 2009

Bibliographical note

Author of Publication Reviewed: Bailey CP, Oldfield S, Llorente J, Caunt CJ, Teschemacher AG, Roberts L, McArdle CA, Smith FL, Dewey WL, Kelly E, Henderson G
Publisher: Wiley

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