Role of G Protein–Coupled Receptor Kinases 2 and 3 inμ-Opioid Receptor Desensitization and Internalization

Abstract

There is ongoing debate about the role of G protein-coupled receptor kinases (GRKs) in agonist-induced desensitization of the m-opioid receptor (MOPr) in brain neurons. In the present paper, we have used a novel membrane-permeable, small-molecule inhibitor of GRK2 and GRK3, Takeda compound 101 (Cmpd101;

Effect of Tamoxifen and Brain-Penetrant Protein Kinase C and c-Jun N-Terminal Kinase Inhibitors on Tolerance to Opioid-Induced Respiratory Depression in Mice

“…Apart from PKC, it has been suggested that JNK2 plays a role in acute antinociception tolerance to morphine (Melief et al, 2010;Kuhar et al, 2015). However, using the JNK inhibitor SP600125, we and others have been unable to observe any involvement of JNK isoforms in MOPr desensitization and morphine-induced cellular tolerance in locus coeruleus neurons (Levitt and Williams 2012;Lowe et al, 2015) or, as reported in this work, in the maintenance of tolerance to morphine-induced respiratory depression. The involvement of JNK in morphine tolerance may therefore be response-dependent.…”

“…Desensitization induced by morphine, a relatively low-efficacy opioid agonist, is primarily mediated by PKC . However, for high-efficacy agonists, a significant proportion of MOPr desensitization involves receptor phosphorylation by GRK2/3 and arrestin binding (Lowe et al, 2015). We and others have also shown that tolerance to the antinociceptive effects of morphine is mediated in large part by PKC (Inoue and Ueda, 2000;Bohn et al, 2002;Smith et al, 2002Smith et al, , 2007Hull et al, 2010), but that tolerance to high-efficacy agonists is mediated by GRKs (Terman et al, 2004;Hull et al, 2010); however, this does not definitively prove that MOPr desensitization contributes to in vivo tolerance, but only that the same kinases are involved in both phenomena.…”

“…Tolerance to the antinociceptive actions of morphine is mediated by a PKC-dependent mechanism, probably involving PKC a, g, and « isoforms (Smith et al, 2007). In contrast, for high intrinsic efficacy opioid agonists, MOPr desensitization, cellular tolerance, and tolerance to antinociception appear to involve G proteincoupled receptor kinases (GRK) (Terman et al, 2004;Johnson et al, 2006;Bailey et al, 2009a;Hull et al, 2010;Lowe et al, 2015).…”

Small-Molecule G Protein–Coupled Receptor Kinase Inhibitors Attenuate G Protein–Coupled Receptor Kinase 2–Mediated Desensitization of Vasoconstrictor-Induced Arterial Contractions

“…Firstly, we used the Takeda compound 101, which is a highly selective GRK2/3 inhibitor especially against other GRK family members, PKA and PKC (Lowe et al, 2015;Thal et al, 2011). Indeed, at the concentrations utilised in this study Takeda compound 101 is unlikely to interact with other kinases that may desensitize UTP-or AngII-mediated contractions (Thal et al, 2011).…”

“…Furthermore, all the compounds used are competitive inhibitors of the GRK2 ATP binding site and since ATP concentrations are likely higher in cells than in vitro assays, this will potentially underestimate kinase inhibition in whole cells. Therefore, it is not surprising that in cellular systems and tissues higher μM concentrations are required to produce maximal effects on kinase inhibition (Lowe et al, 2015).…”