Regulation of Clathrin-Coated Pits by the Mu-Opioid Receptor

描述（由申请人提供）：吗啡等阿片类药物成瘾是一个主要的公共卫生问题。阿片成瘾的复杂病理可通过激活大脑中的特定药物靶点而启动，滥用药物的主要靶点是mu-阿片受体（MOR），它是G蛋白偶联受体（GPCR）家族的成员。gpcr的激活引发一系列事件，导致受调节的受体通过内吞作用从细胞表面移除。在MOR的情况下，受体内吞作用控制神经元对MOR信号反应的去敏化和再敏化，并影响导致药物耐受性和依赖性发展的长期细胞变化。传统观点认为受体内吞作用的调节是通过控制受体与内吞机制的相互作用来实现的，而我最近的研究发现了一种新的机制，通过这种机制，包括MOR在内的gpcr通过控制局部内吞机制来特异性地调节自身的内吞作用。这表明了阿片类药物调节的一个新的和意想不到的方面。拟议的研究旨在确定这种调节的机制基础，并研究其对临床相关阿片类药物作用的功能意义。具体而言，本提案旨在：1)确定介导内吞机制调节的MOR结构决定因素；2)通过鉴定内吞调节蛋白，建立其机制基础；3)确定不同阿片类药物对生理相关神经元这一调控的影响；4)定义这种调控对MOR信号传导的功能后果。申请人有细胞生物学和生物化学方面的培训，并致力于在神经精神疾病和药物成瘾的细胞神经生物学方面进行独立研究。他将接受Mark von Zastrow博士的指导，学习与这些疾病有关的信号受体的药理学、分子遗传学和神经生物学。相关：这些研究的结果将提供对关键阿片受体调节的新模式的见解，并提高我们对药物耐受性和依赖性发展的理解。因此，它们有潜力作为一个平台，设计更好、更明智的治疗策略，以对抗神经精神疾病和药物成瘾。此外，所定义的一般原则可能对各种病理条件下的信号事件具有广泛的含义。

DESCRIPTION (provided by applicant): Addiction to opioid drugs such as morphine is a major public health concern. The complex pathology of opioid addiction can be initiated by activation of specific drug targets in the brain, and the main target of abused drugs is the mu- opioid receptor (MOR), a member of the G protein-coupled receptor (GPCR) family. Activation of GPCRs elicits a sequence of events that results in regulated receptor removal from the cell surface by endocytosis. In the case of MOR, receptor endocytosis controls the de-sensitization and re-sensitization of the neuronal response to MOR signaling, and affects the long-term cellular changes that lead to the development of drug tolerance and dependence. While the traditional view is that regulation of receptor endocytosis is achieved by controlling receptor interaction with the endocytic machinery, my recent studies have identified a novel mechanism by which GPCRs, including MOR, specifically modulate their own endocytosis by controlling the local endocytic machinery. This suggests a novel and unanticipated facet of opioid regulation. The proposed studies seek to identify the mechanistic basis of this regulation and to investigate its functional significance to the effects of clinically relevant opioid drugs. Specifically, this proposal aims to: 1) identify structural determinants on MOR that mediate regulation of the endocytic machinery; 2) establish its mechanistic basis by identifying endocytic regulatory proteins; 3) determine the effect of different opioid drugs on this regulation in physiologically relevant neurons; and 4) define the functional consequences of this regulation on MOR signaling. CANDIDATE: The applicant has prior training in cell biology and biochemistry, and is committed to pursuing independent research in the cellular neurobiology of neuropsychiatric disorders and drug addiction. He will be mentored by Dr. Mark von Zastrow in the pharmacology, molecular genetics, and neurobiology of signaling receptors implicated in these disorders. RELEVANCE: The results of these studies will provide insight into a novel mode of regulation of a key opioid receptor, and improve our understanding of the development of drug tolerance and dependence. Thus they have the potential to serve as a platform for designing better and more informed therapeutic strategies against neuropsychiatric disorders and drug addiction. Further, the general principles defined will likely have broad implications to signaling events underlying a variety of pathological conditions.