Agonist-induced phosphorylation bar code and differential post-activation signaling of the delta opioid receptor revealed by phosphosite-specific antibodies
Abstract The δ-opioid receptor (DOP) is an attractive pharmacological target due to its potent analgesic, anxiolytic and anti-depressant activity in chronic pain models. However, some but not all selective DOP agonists also produce severe adverse effects such as seizures. Thus, the development of no...
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| Autores principales: | , , , , , |
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| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Nature Portfolio
2020
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| Materias: | |
| Acceso en línea: | https://doaj.org/article/7a9660019a0841789184816179841e8c |
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| Sumario: | Abstract The δ-opioid receptor (DOP) is an attractive pharmacological target due to its potent analgesic, anxiolytic and anti-depressant activity in chronic pain models. However, some but not all selective DOP agonists also produce severe adverse effects such as seizures. Thus, the development of novel agonists requires a profound understanding of their effects on DOP phosphorylation, post-activation signaling and dephosphorylation. Here we show that agonist-induced DOP phosphorylation at threonine 361 (T361) and serine 363 (S363) proceeds with a temporal hierarchy, with S363 as primary site of phosphorylation. This phosphorylation is mediated by G protein-coupled receptor kinases 2 and 3 (GRK2/3) followed by DOP endocytosis and desensitization. DOP dephosphorylation occurs within minutes and is predominantly mediated by protein phosphatases (PP) 1α and 1β. A comparison of structurally diverse DOP agonists and clinically used opioids demonstrated high correlation between G protein-dependent signaling efficacies and receptor internalization. In vivo, DOP agonists induce receptor phosphorylation in a dose-dependent and agonist-selective manner that could be blocked by naltrexone in DOP-eGFP mice. Together, our studies provide novel tools and insights for ligand-activated DOP signaling in vitro and in vivo and suggest that DOP agonist efficacies may determine receptor post-activation signaling. |
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