A20 enhances mu-opioid receptor function by inhibiting beta-arrestin2 recruitment

Shao, Shuai; Sun, Yi; Zhang, Yijia; Tian, Xiangyun; Li, Yulei; Tan, Bo; Su, Rui‐Bin

doi:10.1016/j.bbrc.2020.05.073

Cited by 4 publications

(2 citation statements)

References 22 publications

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“…In our study, ABIN-1 had no effect on morphine tolerance in β-arrestin2-KO mice (Fig 4), which suggests that ABIN-1 may alleviate morphine tolerance through down-regulation of β-arrestin2 expression. Additionally, it has been reported that A20, the interacting protein of ABIN-1, attenuated morphine tolerance (Huang et al, 2019) and enhanced MOR function by inhibiting β-arrestin2 recruitment (Shao et al, 2020). Therefore, ABIN-1 and A20 may work together to participate in mediating morphine tolerance.…”

Section: Discussionmentioning

confidence: 99%

A20-Binding Inhibitor of Nuclear Factor-κB Targets β-Arrestin2 to Attenuate Opioid Tolerance

Zhang¹,

Zhou²,

Lu³

et al. 2021

Mol Pharmacol

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Opioids play an important role in pain relief, but repeated exposure results in tolerance and dependence. To make opioids more effective and useful, research in the field has focused on reducing the tolerance and dependence for chronic pain relief.Here, we showed the effect of ABIN-1 in modulating morphine function. We used hotplate tests and CPP tests to show that overexpression of ABIN-1 in the mice brain attenuated morphine dependence. These effects of ABIN-1 are most likely mediated through the formation of ABIN-1-β-arrestin2 complexes, which accelerate β-arrestin2 degradation by ubiquitination. With the degradation of β-arrestin2, ABIN-1 overexpression also decreased MOR phosphorylation and internalization following opioid treatment, affecting the β-arrestin2-dependent signaling pathway to regulate morphine tolerance. Importantly, the effect of ABIN-1 on morphine tolerance was abolished in β-arrestin2 knockout mice. Taken together, these results suggest that the interaction between ABIN-1 and β-arrestin2 inhibits MOR internalization to attenuate morphine tolerance, revealing a novel mechanism for MOR regulation. Hence, ABIN-1 may be a therapeutic target to regulate MOR internalization, thus providing a foundation for a novel treatment strategy for alleviating morphine tolerance and dependence.

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Section: Discussionmentioning

confidence: 99%

A20-Binding Inhibitor of Nuclear Factor-κB Targets β-Arrestin2 to Attenuate Opioid Tolerance

Zhang¹,

Zhou²,

Lu³

et al. 2021

Mol Pharmacol

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“…Opiate effects on paw withdrawal latencies were assessed as the time to response (licking hind paw, quick pedaling, and jumping (s)) after placement on a hot plate maintained at 55 ± 0.5 °C (Shao et al, 2020). To avoid tissue damage, we used a 60 s cutoff.…”

Section: Hot Plate Testmentioning

confidence: 99%

Tyrosine 7.43 is important for mu-opioid receptor downstream signaling pathways activated by fentanyl

Tian¹,

Zhang

Wang

et al. 2022

Front. Pharmacol.

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G protein–coupled receptors can signal through both G proteins and ß-arrestin2. For the µ-opioid receptor (MOR), early experimental evidence from a single study suggested that G protein signaling mediates analgesia and sedation, whereas ß-arrestin signaling mediates respiratory depression and constipation. Then, receptor mutations were used to clarify which residues interact with ligands to selectively regulate signals in a ligand-specific manner. However, there is no systematic study on how to determine these residues and clarify the molecular mechanism of their influence on signal pathways. We have therefore used molecular docking to predict the amino acid sites that affect the binding of ligands and MOR. Then, the corresponding sites were mutated to determine the effect of the structural determinant of MOR on Gi/o protein and ß-arrestin pathways. The pharmacological and animal behavioral experiments in combination with molecular dynamics simulations were used to elucidate the molecular mechanism of key residues governing the signaling. Without affecting ligand binding to MOR, MORY7.43A attenuated the activation of both Gi/o protein and ß-arrestin signaling pathways stimulated by fentanyl, whereas it did not change these two pathways stimulated by morphine. Likewise, the activation peak time of extracellular regulated protein kinases was significantly prolonged at MORY7.43A compared with that at MORwildtype stimulated by fentanyl, but there was no difference stimulated by morphine. In addition, MORY7.43A significantly enhanced analgesia by fentanyl but not by morphine in the mice behavioral experiment. Furthermore, the molecular dynamics simulations showed that H6 moves toward the cellular membrane. H6 of the fentanyl–Y7.43A system moved outward more than that in the morphine–Y7.43A system. Y7.43 mutation disrupted hydrophobic interactions between W6.48 and Y7.43 in the fentanyl–Y7.43A system but not in the morphine–Y7.43A system. Our results have disclosed novel mechanisms of Y7.43 mutation affecting MOR signaling pathways. Y7.43 mutation reduced the activation of the Gi/o protein pathway and blocked the ß-arrestin2 recruitment, increased the H6 outward movement of MOR, and disrupted hydrophobic interactions. This may be responsible for the enhanced fentanyl analgesia. These findings are conducive to designing new drugs from the perspective of ligand and receptor binding, and Y7.43 is also expected to be a key site to structure optimization of synthesized compounds.

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Toll-Like Receptor 4 in Pain: Bridging Molecules-to-Cells-to-Systems

Mustafa

Evans

Barry

et al. 2022

Toll-Like Receptors in Health and Disease

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A20 enhances mu-opioid receptor function by inhibiting beta-arrestin2 recruitment

Cited by 4 publications

References 22 publications

A20-Binding Inhibitor of Nuclear Factor-κB Targets β-Arrestin2 to Attenuate Opioid Tolerance

A20-Binding Inhibitor of Nuclear Factor-κB Targets β-Arrestin2 to Attenuate Opioid Tolerance

Tyrosine 7.43 is important for mu-opioid receptor downstream signaling pathways activated by fentanyl

Toll-Like Receptor 4 in Pain: Bridging Molecules-to-Cells-to-Systems

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