Research ArticleGPCR SIGNALING

Multisite phosphorylation is required for sustained interaction with GRKs and arrestins during rapid μ-opioid receptor desensitization

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Science Signaling  17 Jul 2018:
Vol. 11, Issue 539, eaas9609
DOI: 10.1126/scisignal.aas9609

Controlling opioid receptor desensitization

Chronic opioid use leads to tolerance and the need for increasing doses to achieve pain relief, euphoria, and other effects. At the molecular level, tolerance occurs because of μ-opioid receptor desensitization: Opioid activation of its receptors triggers their phosphorylation and internalization, ultimately reducing the cellular response to opioids. Miess et al. investigated why high-efficacy opioids induce greater receptor internalization than lower-efficacy opioids such as morphine. The kinase GRK2 and the scaffolding protein β-arrestin regulate the desensitization of opioid receptors and other G protein–coupled receptors, and the authors assessed the recruitment of GRK2 and β-arrestin to phosphorylation site receptor mutants. GRK2 was more rapidly recruited to μ-opioid receptors by high-efficacy opioids than by morphine, and GRK2 promoted receptor desensitization to high-efficacy opioids through phosphorylation-dependent and phosphorylation-independent means. These results provide molecular insight into μ-opioid receptor desensitization, which may aid in the development of synthetic opioids that do not induce tolerance and thus have reduced potential for addiction.

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