Cellular Pharmacology of Kappa Opiod Receptor

Kappa 阿片受体的细胞药理学

基本信息

批准号：
8459584
负责人：
LEE-YUAN LIU-CHEN
金额：
$ 27.66万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-05-01 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8459584
关键词：
14-3-3 Proteins ATP phosphohydrolase Abbreviations Absence of pain sensation Adenylate Cyclase Adrenergic Receptor Affect Agonist Amino Acids Anabolism Anti-Anxiety Agents Applications Grants Autophagocytosis Binding Binding Proteins Brefeldin A C-terminal Cell Line Cell Surface Receptors Cell membrane Cell surface Cells Cellular biology Chemicals Chinese Hamster Ovary Cell Coat Protein Complex I Coatomer Protein Cocaine Complementary DNA Coupled Cyclodextrins Diuresis Dominant-Negative Mutation Down-Regulation Dynorphin A Ear Embryo Endocytosis Pathway Endoplasmic Reticulum Endosomes Enhancers Epitopes Equilibrium Event Familiarity Family G Protein-Coupled Receptor Genes G-Protein-Coupled Receptors GTP-Binding Proteins Glutathione S-Transferase Golgi Apparatus Hemagglutinin Horseradish Peroxidase Human Immune response Kidney Light Lipids Lysosomes MAP Kinase Gene Masks Mediating Membrane Microtubule-Associated Proteins Mitogen-Activated Protein Kinases Modification Molecular Chaperones Mus N-ethylmaleimide-sensitive protein Neurotensin Receptors Neurotransmitters Opioid Opioid Receptor Pain Pathway interactions Peptides Pertussis Toxin Pharmaceutical Preparations Pharmacology Phosphoproteins Physiological Play Polyacrylamide Gel Electrophoresis Prostaglandin Receptor Protein Family Proteins Proto-Oncogene Proteins c-raf Quality Control Rattus Recycling Regulation Research Rhodopsin Role Signal Transduction Signaling Molecule Sodium Dodecyl Sulfate-PAGE Sorting - Cell Movement Specificity Stimulus Tail Techniques Testing Transcription Coactivator Transmembrane Domain Visceral Water Yeasts base craving delta opioid receptor dysphoria ezrin glycosylation golgi associated, gamma adaptin homologous, ADP-ribosylation factor interacting protein in vivo insight member moesin mu opioid receptors mutant natural hypothermia novel programs protein complex radixin protein receptor receptor binding receptor expression research study response sodium-hydrogen exchanger regulatory factor sortilin trafficking trans-Golgi Network

项目摘要

The ¿ opioid receptor (KOPR) is one of the three major types (¿, ¿ and ¿) of opioid receptors that mediate effects of opioids in vivo. Activation of KOPR produces analgesia, dysphoria, water diuresis, hypothermia and modulation of immune responses. KOPR antagonists may be potentially useful for curbing cocaine craving and as anti-depressants and anti-anxiety agents. KOPR, a member of the 7TMR family, is coupled through pertussis toxin-sensitive G proteins to a variety of effectors. For 7TMRs. the capacity of agonists to modulate downstream signaling molecules depends on the availability of the receptors on cell surface. The number of cell surface 7TMRs reflects a balance between biosynthesis and endocytosis pathways. The post-activation endocytic events have been well-documented; however, regulation along the biosynthesis pathway is much less understood. The focus of this grant application is to characterize the regulation of the KOPR trafficking along the biosynthesis pathway, in particular by the proteins GEC1, sortilin and 14-3-3 proteins, which we found to interact with the KOPR and to be involved in KOPR export trafficking. The central hypothesis is that the export trafficking is regulated by molecules interacting with the KOPR. The specific aims are as follows. (1) To delineate mechanisms underlying GEC1-promoted expression and trafficking of the KOPR. The hypothesis that GEC1 enhances KOPR expression by enhancing ATPase activity of NSF, but not by membrane association by lipid conjugation will be tested. (2) To investigate the role of 14-3-3 in the trafficking and cellular pharmacology of the KOPR. The hypothesis is that 14-3-3 proteins bind to KOPR C-terminal domain and/or i3 loop, which masks COPI binding, allowing the KOPR to sort to plasma membranes. (3) To examine the interaction of the KOPR with sortilin and its functional consequences. The hypothesis to be tested is that sortilin binding to the KOPR sorts the receptor to endosomes and lysosomes and this represents a novel post-ER quality control mechanism. We will also examine if the interactions of the KOPR with these proteins affect signaling and regulation. The proposed studies will provide better understanding of cell biology of the KOPR and provide mechanistic insights into regulation of export of the KOPR. In addition, such understanding will have important implications for other membrane bound receptors since these regulatory mechanisms of export are likely to be applicable to some other proteins.

这阿片受体 (KOPR) 是介导阿片受体的三种主要类型（¿、¿ 和 ¿）之一阿片类药物在体内的作用 KOPR 的激活会产生镇痛、烦躁、利尿、体温过低和 KOPR 拮抗剂的免疫反应调节可能有助于抑制可卡因渴望。作为抗抑郁药和抗焦虑药，KOPR 是 7TMR 家族的成员，通过偶联。百日咳毒素敏感 G 蛋白对多种效应物的调节作用。下游信号分子取决于细胞表面受体的数量。细胞表面 7TMR 反映了生物合成和内吞途径之间的平衡。内吞事件已被充分记录；然而，沿生物合成途径的调节有很多。这项拨款申请的重点是描述 KOPR 贩运的监管特征。沿着生物合成途径，特别是通过蛋白质 GEC1、分拣蛋白和 14-3-3 蛋白质，我们被发现与 KOPR 互动并参与 KOPR 出口贩运核心假设是：出口贩运受到与 KOPR 相互作用的分子的调节，具体目标如下。 (1) 描述 GEC1 促进 KOPR 表达和运输的机制。假设 GEC1 通过增强 NSF 的 ATPase 活性来增强 KOPR 表达，而不是通过将测试通过脂质缀合的膜缔合 (2) 研究 14-3-3 在运输中的作用。 KOPR 的细胞药理学假设是 14-3-3 蛋白与 KOPR C 末端结合。 (3) 至检查 KOPR 与分拣蛋白的相互作用及其功能后果。经测试，分拣蛋白与 KOPR 结合可将受体分类到内体和溶酶体，并且这代表了一种新颖的后 ER 质量控制机制，我们还将研究 KOPR 是否相互作用。拟议的研究将提供对这些蛋白质影响信号传导和调节的更好理解。 KOPR 的细胞生物学，并为 KOPR 的输出调控提供机制见解。这种理解将对其他膜结合受体产生重要影响，因为这些出口监管机制可能适用于其他一些蛋白质。