Role of G Protein-Coupled Receptor Kinases 2 and 3 in μ-Opioid Receptor Desensitization and Internalization

Janet D. Lowe, Helen S. Sanderson, Alexandra E. Cooke, Mehrnoosh Ostovar, Elena Tsisanova, Sarah L. Withey, Charles Chavkin, Stephen M. Husbands, Eamonn Kelly, Graeme Henderson, Chris P. Bailey

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There is ongoing debate about the role of G protein receptor kinases (GRKs) in agonist-induced desensitization of the μ opioid receptor (MOPr) in brain neurons (see Williams et al., 2013, Pharmacol Rev 15;223-254). In the present paper we have used a novel, membrane permeable, small molecule inhibitor of GRK2 and GRK3, Takeda Compound 101 (Cmpd101), to study the involvement of GRK2/3 in acute agonist-induced MOPr desensitization. We observed that Cmpd101 inhibits the desensitization of the G protein activated potassium current (GIRK) evoked by receptor- saturating concentrations of methionine enkephalin (Met Enk), D-Ala2,N-MePhe4,Gly-ol]-enkephalin (DAMGO), endomorphin-2 and morphine in rat and mouse locus coeruleus (LC) neurons. In LC neurons from GRK3 knockout mice Met Enk-induced desensitization was unaffected implying a role for GRK2 in MOPr desensitization. Quantitative analysis of the loss of functional MOPrs following acute agonist exposure revealed that Cmpd101 only partially reversed MOPr desensitization. Inhibition of ERK1/2, PKC, JNK or GRK5 did not inhibit the Cmpd101-insensitive component of desensitization. In HEK 293 cells Cmpd101 produced almost complete inhibition of DAMGO-induced MOPr phosphorylation at Ser375, arrestin translocation and MOPr internalization. Our data demonstrate a role for GRK2 (and potentially also GRK3) in agonist-induced MOPr desensitization in the LC, but leave open the possibility that another, as yet unidentified, mechanism of desensitization also exists.

Original languageEnglish
Pages (from-to)347-356
JournalMolecular Pharmacology
Issue number2
Early online date26 May 2015
Publication statusPublished - Aug 2015

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The American Society for Pharmacology and Experimental Therapeutics.


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