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

SUIVILVlARY：对阿片类药物上瘾，如吗啡，是一个主要的公共卫生问题。情结 阿片成瘾的病理机制可以通过激活大脑中的特定药物靶点来启动，而主要的 滥用药物的靶标是U-阿片受体(Mor)，它是G蛋白偶联受体的成员 (GPCR)家系。GPCRs的激活引发一系列事件，导致受调控的受体移除 通过内吞作用从细胞表面排出。在MOR的情况下，受体内吞作用控制着脱敏 和对MOR信号的神经元反应的再敏化，并影响细胞的长期变化 这会导致药物耐受性和依赖性的发展。虽然传统观点认为监管 受体内吞作用的实现是通过控制受体与内吞机制的相互作用，我的 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GPCRs特异性地调节 他们自己的内吞作用是通过控制当地的内吞机制实现的。这让人联想到一种新奇而出人意料的 阿片类药物调控的一个方面。拟议的研究试图确定这一规定的机制基础，并 探讨其对临床相关阿片类药物疗效的作用意义。具体地说，这项建议的目的是：1)确定和提炼介导内吞机制调节的MOR结构决定因素；2)通过识别内吞调节蛋白来建立其机制基础；3)确定不同阿片类药物对生理相关神经元中这种调节的影响；以及4)确定这一调节对MOR信号的功能后果。应聘者：曾接受过细胞生物学和生物化学方面的培训，致力于神经精神障碍和药物成瘾的细胞神经生物学方面的独立研究。在K99阶段，马克·冯·扎斯特罗博士指导他研究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，

SUIVilVlARY: Addiction to opioid drugs sucli 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 and refine the 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. In the K99 phase, he has been mentored by Dr. Mark von Zastrow in the pharmacology, molecular genetics, and neurobiology of signaling receptors implicated in these disorders,