Dynamic Mechanisms of GPCRs Targeted by Drugs of Abuse

描述(申请人提供)：仅在美国就有200多万人已知滥用阿片类止痛药，对这些药物的上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，主要介导临床上使用的阿片类止痛药的作用。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MOR信号、磷酸化、脱敏和内化，对其生理反应，包括镇痛耐受的发展具有重要意义。最近提出的MOR寡聚可以调节受体结合、信号传递和/或运输的建议，进一步复杂化了我们对MOR介导的功能的理解。本申请中提出的研究的总体目标是揭示在MOR观察到的功能选择性背后的分子机制。这些信息对于确保MOR信号微调到所需的治疗途径而不是那些调节不良副作用的信号是重要的，最终目标是发现非成瘾性止痛药。这项拨款申请中提出的计算研究利用理论和实验的前沿发展，以前所未有的分子细节水平获得对膜中MOR的结构、时空组织和动力学的严格机制洞察，从而拓宽了目前对MOR偏向激动症的理解。具体地说，我们将提供目前不可能或难以通过实验检索的MOR稀疏状态的结构和动态信息，从而产生可测试的假说，即不同的阿片类药物如何在分子水平上诱导MOR的差异寡聚和信号传递，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，将促进我们目前对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。从这一应用中产生的数据将被添加到关于GPCR寡聚的其他相关最新信息中，并进一步填充我们最近部署的GPCR-寡聚知识库系统，以继续促进和支持研究涉及药物滥用的GPCRs的计算科学家和实验科学家之间的富有成效的合作。 公共卫生相关性：我们研究的目标是了解阿片受体不同生理功能的分子机制，以最终开发出没有副作用的止痛药。

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. PUBLIC HEALTH RELEVANCE: The goal of our research is to understand the molecular mechanisms underlying the diverse physiological functions of mu-opioid receptors to ultimately develop analgesics that are free from side effects.