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

Mu-阿片受体对网格蛋白包被凹坑的调节

基本信息

批准号：
8132904
负责人：
Manojkumar A Puthenveedu
金额：
$ 23.91万
依托单位：
CARNEGIE-MELLON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-06-01 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8132904
关键词：
Address Adenylate Cyclase Affect Agonist Award Binding Biochemistry Brain C-terminal Cell surface Cells Cellular Neurobiology Cellular biology Clathrin Commit Complex Cytoplasmic Tail Cytoskeleton Development Disease Drug Addiction Drug Delivery Systems Drug Tolerance Elements Endocytosis Enkephalin, Ala(2)-MePhe(4)-Gly(5)-Enkephalins Event Excision Family Future G-Protein-Coupled Receptors Lead Leucine Life Ligands Link MAPK3 gene Mediating Mentors Methadone Mitogen-Activated Protein Kinases Molecular Genetics Morphine Neurobiology Neurons Neuropeptide Receptor Opiate Addiction Opioid Opioid Peptide Opioid Receptor Pathology Pharmaceutical Preparations Pharmacology Phase Physiological Play Proteins Proteomics Public Health Receptor Signaling Regulation Research Role Signal Pathway Signal Transduction Staging System Tail Testing Therapeutic Training Vesicle Work addiction analog base cellular imaging clinically relevant coated pit delta opioid receptor design drug of abuse genetic regulatory protein improved insight member mu opioid receptors neuropsychiatry novel opioid abuse receptor research study response

项目摘要

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,

Suivilvlary：对阿片类药物的成瘾sucli作为吗啡是一个主要的公共卫生问题。综合体阿片类药物成瘾的病理可以通过激活大脑中的特定药物靶标而引发滥用药物的靶标是Mu阿片类受体（MOR），G蛋白偶联受体的成员（GPCR）家庭。 GPCR的激活引发了一系列事件，导致受体去除通过内吞作用从细胞表面。对于MOR，受体内吞作用控制去敏化以及对MOR信号的神经元反应的重新敏化，并影响长期的细胞变化这导致了药物耐受性和依赖性的发展。而传统观点是该法规受体内吞作用是通过控制与内吞机械的受体相互作用来实现的最近的研究已经确定了一种新的机制，其中包括MOR在内的GPCR特别调节了该机制通过控制局部内吞机器，它们自己的内吞作用。这暗示了一部小说和意外的阿片类药物调节的方面。拟议的研究旨在确定该法规的机械基础，并研究其功能意义对临床相关的阿片类药物的影响。具体而言，该提案的目的是：1）确定和完善MOR上介导内吞机械调节的结构决定因素； 2）通过鉴定内吞调节蛋白来确定其机械基础； 3）确定不同阿片类药物对生理相关神经元调节的影响； 4）定义该调节对MOR信号传导的功能后果。候选人：申请人先前接受过细胞生物学和生物化学的培训，并致力于从事神经精神疾病和药物成瘾的细胞神经生物学方面的独立研究。在K99阶段，他是由马克·冯·扎斯特罗（Mark von Zastrow）博士指导的，这些信号受体的药理学，分子遗传学和神经生物学与这些疾病有关，