Modulation of mu-opioid receptor dynamics at the plasma membrane and its implications for signalling and trafficking

质膜μ阿片受体动力学的调节及其对信号传导和运输的影响

• 批准号: 2284193
• 金额: --
• 依托单位: University of Nottingham
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2284193
• 关键词: Modulation; mu; opioid; receptor; dynamics

The mu opioid receptor (MOP) is the target of most commonly used analgesics, such as morphine. Unfortunately, despite opioids being very effective at treating severe pain, they still induce adverse effects that limit their clinical use, including addiction, respiratory depression and constipation. Indeed, misuse of prescription and illicit opioids is the main cause of the dramatic increase in the number of deaths due to overdose caused by respiratory distress, the so-called "opioid epidemic". This illustrates that, despite decades of research, there is a pressing need for a better understanding of opioid receptor signalling and regulation. This project builds from prior observations from our lab that start to delineate the mechanisms that regulate MOP signalling in response to different ligands. These mechanisms include translocation of the receptor within the plasma membrane, its phosphorylation and its dynamic interactions with intracellular proteins such as b-arrestins and protein kinase C (PKC). This project will use a wide range of advanced imaging (Fluorescence correlation spectroscopy, super resolution microscopy) and biophysical techniques (FRET and BRET) combined with classical pharmacology, cell biology and biochemistry approaches to provide further understanding on MOP dynamics and signalling and inform drug development towards the generation of more effective analgesics.

阿片受体（mu opioid receptor， MOP）是吗啡等常用镇痛药的作用靶点。不幸的是，尽管阿片类药物在治疗严重疼痛方面非常有效，但它们仍然会引起不良反应，限制其临床使用，包括成瘾、呼吸抑制和便秘。事实上，处方类阿片和非法类阿片的滥用是因呼吸窘迫而过量服用导致死亡人数急剧增加的主要原因，即所谓的“类阿片流行病”。这表明，尽管经过数十年的研究，迫切需要更好地了解阿片受体的信号传导和调节。该项目建立在我们实验室先前的观察基础上，开始描述针对不同配体调节MOP信号传导的机制。这些机制包括受体在质膜内的易位，其磷酸化及其与细胞内蛋白质（如b-阻滞蛋白和蛋白激酶C (PKC)）的动态相互作用。该项目将使用广泛的先进成像技术（荧光相关光谱，超分辨率显微镜）和生物物理技术（FRET和BRET），结合经典药理学，细胞生物学和生物化学方法，进一步了解MOP动力学和信号，并为药物开发提供信息，以产生更有效的镇痛药。