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

阿片类药物成瘾，如吗啡，是一个主要的公共卫生问题。复杂 阿片类成瘾的病理学可以通过激活大脑中的特定药物靶点来启动，并且主要 滥用药物的靶点是μ阿片受体（莫尔），它是G蛋白偶联受体的一个成员 （GPCR）家族。GPCR的激活引发一系列事件，导致受调节的受体去除 通过内吞作用从细胞表面分离。在莫尔的情况下，受体内吞作用控制去敏感化 并使神经元对莫尔信号的反应重新敏感，并影响长期的细胞变化 导致药物耐受性和依赖性的发展。传统观点认为， 受体的内吞作用是通过控制受体与内吞机制的相互作用来实现的， 最近的研究已经确定了一种新的机制，通过这种机制，GPCR，包括莫尔，特异性地调节 通过控制局部内吞机制来控制自身的内吞作用。这意味着一个新的和意想不到的 阿片类药物的调节。拟议的研究旨在确定这一规定的机械基础， 探讨其对临床相关阿片类药物作用的功能意义。具体而言，该提案旨在：1）鉴定和完善介导内吞机制调节的莫尔结构决定因素; 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中该调节的影响;以及4）定义该调节对莫尔信号传导的功能后果。候选人：申请人在细胞生物学和生物化学方面接受过培训，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。在K99阶段，Mark von Zastrow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,