Dynamic Mechanisms of GPCRs Targeted by Drugs of Abuse

描述（由申请人提供）：仅在美国就有超过200万人滥用基于阿片类药物的止痛药，这些药物成瘾是一个重大的公共卫生问题。mu-阿片受体（MOR）是G蛋白偶联受体（GPCR）家族的成员，主要介导临床使用的阿片镇痛药的作用。基于过去几十年的大量体外和体内研究，越来越清楚的是，阿片配体可以产生不同的信号，磷酸化，脱敏和MOR的内化，对其生理反应具有重要影响，包括镇痛耐受性的发展。最近关于MOR寡聚化可以调节受体结合、信号传导和/或运输的研究进一步使我们对MOR介导功能的理解复杂化。在本应用中提出的研究的总体目标是揭示在MOR中观察到的功能选择性的分子机制。这一信息对于确保MOR信号朝着理想的治疗途径进行微调，但远离那些介导不良副作用的信号非常重要，最终目标是发现非成瘾性镇痛剂。本基金申请中提出的计算研究利用了理论和实验的前沿发展，在前所未有的分子细节水平上，对膜中MOR的结构、时空组织和动力学进行了严格的机制洞察，从而拓宽了目前对MOR偏向性激动作用的理解。具体来说，我们将提供关于MOR稀疏状态的结构和动态信息，这些信息目前不可能或难以通过实验获得，从而产生可测试的假设，即在分子水平上，不同的阿片类药物如何诱导MOR的差异寡聚化和信号传导，从而导致药物的特定行为效应。通过与独立资助的实验室合作，对这些计算预测进行实验验证，将推进我们目前对MOR功能基本机制的理解，并为针对药物滥用和成瘾的新治疗策略铺平道路。从这个应用程序中产生的数据将被添加到其他有关GPCR寡聚化的最新信息中，并进一步填充我们最近部署的GPCR寡聚化知识库系统，以继续促进和支持研究与药物滥用有关的GPCR的计算和实验科学家之间的有效合作。

DESCRIPTION (provided by applicant): With over 2 million people in the United States alone known to abuse opioid-based pain medications, addiction to these drugs represents a significant public health concern. The mu-opioid receptor (MOR) is the member of the G protein-coupled receptor (GPCR) family that primarily mediates the actions of clinically used opioid- based analgesics. Based on extensive in vitro and in vivo work over the past decades, it has become increasingly clear that opioid ligands can produce different signaling, phosphorylation, desensitization, and internalization of MOR, with major implications for its physiological responses, including the development of analgesic tolerance. The recent suggestion that MOR oligomerization can modulate receptor binding, signaling, and/or trafficking further complicates our understanding of MOR-mediated function. The overall goal of the research proposed in this application is to reveal the molecular mechanisms underlying the observed functional selectivity at MOR. This information is important to ensure the fine-tuning of MOR signaling towards desired therapeutic pathways but away from those mediating adverse side effects, with the ultimate goal of discovering non-addictive analgesic agents. The computational research proposed in this grant application takes advantage of cutting-edge developments in theory and experiments to obtain rigorous mechanistic insight, at an unprecedented level of molecular detail, into the structure, spatio-temporal organization, and dynamics of MOR in the membrane, thus broadening current understanding of MOR biased agonism. Specifically, we will contribute structural and dynamic information regarding sparsely-populated states of MOR that are currently impossible or difficult to retrieve experimentally, thereby generating testable hypotheses of how, at the molecular level, different opioids induce differential oligomerization and signaling of MOR, leading to the specific behavioral effects of the drugs. Experimental validation of these computational predictions, to be attained through collaborations with independently funded laboratories, will advance our current understanding of fundamental basic mechanisms of MOR function, and pave the way to novel therapeutic strategies against drug abuse and addiction. The data that will emerge from this application will be added to other relevant recent information on GPCR oligomerization, and further populate our recently deployed GPCR-Oligomerization Knowledge Base system to continue to promote and support productive collaborations between computational and experimental scientists working on GPCRs involved in drug abuse.