Opioid Receptor Signaling: selective mechanism of regulation & receptor crosstalk

阿片受体信号传导：选择性调节机制

• 批准号: 7283341
• 负责人: CHRISTOPHER J. EVANS
• 金额: $ 23.81万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7283341
• 关键词: ARRB2; Absence of pain sensation; Agonist; Alkaloids; Analgesics; Arrestin; Arrestins; Behavioral; Buprenorphine; Cells; Chronic; Confocal Microscopy; Data; Doctor of Philosophy; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Etorphine; Exhibits; Flow Cytometry; Foundations; Funding; GTP-Binding Proteins; Gene Expression; Genes; Genetic; Goals; Ligands; MAP Kinase Gene; Mediating; Methadone; Microtus; Morphine; Mus; Mutant Strains Mice; Neurons; Opioid; Opioid Receptor; Pharmaceutical Preparations; Phosphorylation; Polymerase Chain Reaction; Principal Investigator; Property; Protein Isoforms; Receptor Cross-Talk; Receptor Signaling; Regulation; Research Personnel; Role; SRC gene; Series; Signal Pathway; Signal Transduction; Spinal Ganglia; System; Techniques; Testing; Time; Title; Transcript; abstracting; base; beta-arrestin; cellular targeting; delta opioid receptor; desensitization; inhibitor/antagonist; mu opioid receptors; programs; protein expression; receptor; receptor internalization; response; trafficking; voltage

Principal Investigator/Program Director: Evans, Christopher J., Ph.D., Component II Component II title: Opioid Receptor Signaling: selective mechanisms of regulation and receptor cross-talk ABSTRACT: Component II will study the mechanisms by which mu opioid agonists can trigger differential signaling and receptor trafficking. During the past funding period we have developed mouse dorsal root ganglia (DRG) primary cultures to study both native and virally expressed opioid receptors in wild-type and mutant mice (such as those generated in Component I and others available through the Mutant Mouse Core). The use of real time PCR, gene arrays, flow cytometry and confocal microscopy has enabled us to fully characterize the expression of regulated mRNAs as well as protein expression, distribution, and states of phosphorylation. Using these techniques in combination with electrophysiological recording, we have developed evidence for unique trafficking and signaling profiles for morphine and DAMGO with implication for a major regulatory Vole of arrestin isoforms. Based upon these preliminary data Component II will: 1) Characterize the differential mu-receptor-mediated signaling initially observed with DAMGO and morphine and subsequently define signaling profiles of other clinically important and endogenous agonists; 2) Analyze the contributions of receptor cross-talk via alpha 2a and delta opioid receptors on mu-receptor trafficking and signaling; 3) Test the hypothesis that beta-arrestins, and the cellular targeting of c-src are critical in determining both the opioid agonist signaling-profiles and trafficking of mu opioid receptors. Together these aims will provide a foundation for understanding agonist-directed signaling via mu opioid receptors with the goal of identifying agonist properties that may differentiate the clinically useful from the detrimental effects of opioid drugs.

首席研究员/项目总监：Evans, Christopher J.，博士，第二部分 第二部分标题：阿片受体信号传导：选择性机制 调节和受体串扰 抽象的： 第二部分将研究 mu 阿片类激动剂触发差异信号传导的机制 受体贩运。在过去的资助期间，我们开发了小鼠背根神经节（DRG） 用于研究野生型和突变型小鼠中天然和病毒表达的阿片受体的原代培养物 （例如在组件 I 中生成的组件以及通过 Mutant Mouse Core 获得的其他组件）。用途 实时 PCR、基因阵列、流式细胞术和共聚焦显微镜使我们能够充分表征 受调节 mRNA 的表达以及蛋白质的表达、分布和状态 磷酸化。将这些技术与电生理记录相结合，我们 为吗啡和 DAMGO 的独特贩运和信号传导谱提供了证据，并具有意义 抑制蛋白亚型的主要调节田鼠。根据这些初步数据，第二部分将：1) 表征最初用 DAMGO 和吗啡观察到的差异性 mu 受体介导的信号传导 并随后定义其他临床重要的内源性激动剂的信号传导谱； 2）分析 通过α2a和δ阿片受体的受体串扰对mu受体贩运的贡献 和信号发送； 3) 检验 β-arrestins 和 c-src 的细胞靶向在 确定阿片受体激动剂信号传导谱和 mu 阿片受体的运输。 这些目标共同将为理解 mu 阿片类药物的激动剂导向信号传导奠定基础 受体的目的是识别激动剂的特性，这些特性可以区分临床上有用的药物和实际有效的药物。 阿片类药物的有害作用。