The role of the ubiquitination to the mu-opioid receptor in developing tolerance and adverse effects to opioids.

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K16547
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 55050:Anesthesiology-related
• Research Institution: Kyoto University (2021, 2023); Shiga University of Medical Science (2022)
• Principal Investigator: Satoshi Shimizu 京都大学, 医学研究科, 客員研究員 (80802793)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: オピオイド受容体 / 耐性形成 / Gタンパク質共役型受容体 / ユビキチン修飾 / 受容体内在化

Outline of Final Research Achievements

Opioids are highly potent analgesics but develop tolerance. Previous studies have focused on phosphorylation to μ-opioid receptor as it is involved in maintaining cellular sensitivity via desensitization, recycling and degradation of the activated receptor. Recently, another form of post-translational modification of ubiquitination has attracted attention in terms of triggering intracellular signaling and regulation of the activated receptor. Here, we generated a ubiquitination-deficient mutant of the μ-opioid receptor to investigate whether ubiquitination is involved in driving Gi/o-mediated analgesic signaling, receptor desensitization or subsequent receptor internalization. We show that the Gi/o pathway and receptor phosphorylation do not require ubiquitination. Instead, ubiquitination regulates the internalization efficiency and might help promote internalization of the desensitized MOP.

Free Research Field

麻酔科学

Academic Significance and Societal Importance of the Research Achievements

オピオイドは非常に強力な鎮痛薬であるが、耐性を形成するために長期的には効果が減弱する場合がある。近年、がん治療が進歩して生命予後が改善している一方で、がんの疼痛が十分に緩和されていないケースが増えており、耐性形成機構の解明は重要な課題である。先行研究では、受容体へのリン酸化が受容体の脱感作や分解・再利用経路へと導く細胞内内在化において重要な役割を果たすことが注目されてきた。本研究では、リン酸化修飾だけでは機序の説明がつきにくい点に着目し、ユビキチン修飾が脱感作された受容体を分解・再利用経路へと導く第一段階となる内在化を効率的に行う上で重要な役割を果たすことを見出した。