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.

首席调查员/计划主任：埃文斯（Evans），克里斯托弗·J·J·德（Christopher J. 组件II标题：阿片类药物受体信号传导：选择性机制 调节和受体串扰 抽象的： 组件II将研究MU阿片类动力学家触发差异信号传导和 受体贩运。在过去的资金期间，我们开发了小鼠背根神经节（DRG） 在野生型和突变小鼠中研究天然和病毒表达的阿片受体的主要培养物 （例如在组件I中生成的那些以及通过突变小鼠核心可用的其他产品）。使用 实时PCR，基因阵列，流式细胞仪和共聚焦显微镜的效果使我们能够完全表征 受调节的mRNA的表达以及蛋白质表达，分布和状态 磷酸化。将这些技术与电生理记录结合使用，我们有 为吗啡和Damgo提供了独特的贩运和信号传导概况的证据 用于抑制素同工型的主要调节性。基于这些初步数据组件II将：1） 表征最初用DAMGO和吗啡观察到的差异MU受体介导的信号传导 随后定义了其他临床重要和内源性激动剂的信号传导谱； 2）分析 通过α2A和三角洲阿片受体对MU受体运输的受体串扰的贡献 和信号传导； 3）检验以下假设：beta-arrestins和c-Src的细胞靶向至关重要 确定阿片类激动剂信号传导和MU阿片受体的运输。 这些目标共同为通过MU阿片类药物理解激动剂指导的信号提供基础 受体的目的是识别可能将临床上有用的激动剂特性与 阿片类药物的有害作用。