Regulated degradation of EF2K: linking neuronal protein synthesis and turnover

EF2K 的调控降解：连接神经元蛋白质合成和周转

• 批准号: 8058062
• 负责人: Shari Lenore Wiseman
• 金额: $ 3.54万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8058062
• 关键词: Area; Behavior; Behavioral; Biological Models; Brain; Ca(2+)-Calmodulin Dependent Protein Kinase; Calcium/calmodulin-dependent protein kinase; Cells; Chronic; Cocaine; Cyclic AMP; Cycloheximide; Cytoplasm; Data; Development; Dose; Elements; Equilibrium; Genes; Genetic Translation; Goals; Hippocampus (Brain); Insulin-Like Growth Factor I; Investigation; Link; Mediating; Mediator of activation protein; Memory; Messenger RNA; Molecular; Nerve Growth Factors; Neurons; PC12 Cells; Pattern; Peptide Elongation Factor 2; Pharmaceutical Preparations; Phase; Phosphorylation; Phosphorylation Site; Phosphotransferases; Polyubiquitination; Process; Protein Biosynthesis; Protein Kinase; Protein Synthesis Inhibitors; Proteins; Proteomics; Regulation; Research; Rewards; Role; Synapses; Synaptic plasticity; System; Translating; Translations; Ubiquitin; addiction; base; calmodulin-dependent protein kinase III; drug of abuse; gene function; inhibitor/antagonist; multicatalytic endopeptidase complex; novel; novel strategies; novel therapeutics; protein degradation; protein expression; psychostimulant; relating to nervous system; response; reward circuitry; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): Proper neuronal function requires precise temporal and spatial regulation of protein levels, and this is largely occurs via control over the translation of mRNAs into new proteins and the degradation of existing proteins by the ubiquitin-proteasome system (UPS). Studies using pharmacological inhibitors of protein synthesis and the UPS have indicated that these processes are critical for long-term synaptic plasticity and memory consolidation, and regulation of these processes is likely involved in the plasticity of brain reward systems that mediates the development of addiction. Emerging evidence suggests that stabilization of long-term plasticity requires gene-specific, rather than global, translational control and coordination or balance of protein synthesis and degradation processes. The mechanisms by which this occurs, the specific changes in protein expression that result, and the consequences of these processes for drug-mediated behavior are critical issues that this proposal seeks to elucidate by investigating the role and regulation of eukaryotic elongation factor-2 kinase, a Ca2????dependent protein kinase that exerts translational control by phosphorylating eukaryotic elongation factor-2 (eEF-2) and inhibiting translation at the elongation step. Previous studies and preliminary data suggest that EF2K is a central mediator both of gene-specific translation and the coordination of protein synthesis and degradation, although the mechanisms and consequences of these functions remain to be elucidated. To this end, the proposed research will characterize the mechanisms by which EF2K is targeted for UPS-mediated degradation in response to stimulation, the specific regulation that EF2K exerts on patterns of protein expression, and the role of EF2K in locomotor sensitization to cocaine. These studies will advance understanding of the role of gene-specific modes of translation and coordination of protein synthesis and degradation, as well as the mechanisms of plasticity mediated by drugs of abuse, potentially enabling the development of novel therapeutics. PUBLIC HEALTH RELEVANCE: The goal of this proposal is to characterize the function of gene-specific translational control and coordination of protein synthesis and degradation in cocaine-mediated behavior, the mechanisms by which these processes occur, and their specific consequences for patterns of protein expression. The long-term changes in neural reward circuitry that underlie addiction are thought to engage these molecular processes, and by characterizing them in detail, novel approaches to the treatment of addiction may be developed.

描述（由申请人提供）：适当的神经元功能需要对蛋白质水平进行精确的时间和空间调节，这主要是通过控制 mRNA 翻译成新蛋白质以及泛素蛋白酶体系统 (UPS) 对现有蛋白质的降解来实现的。使用蛋白质合成和 UPS 的药理学抑制剂的研究表明，这些过程对于长期突触可塑性和记忆巩固至关重要，并且这些过程的调节可能涉及介导成瘾发展的大脑奖励系统的可塑性。新的证据表明，长期可塑性的稳定需要基因特异性而非全局的翻译控制以及蛋白质合成和降解过程的协调或平衡。这种情况发生的机制、所导致的蛋白质表达的具体变化以及这些过程对药物介导的行为的影响是本提案试图通过研究真核延伸因子2激酶的作用和调节来阐明的关键问题，一种 Ca2+依赖性蛋白激酶，通过磷酸化真核延伸因子 2 (eEF-2) 并在延伸步骤抑制翻译来发挥翻译控制作用。先前的研究和初步数据表明，EF2K 是基因特异性翻译以及蛋白质合成和降解协调的中心介质，尽管这些功能的机制和后果仍有待阐明。为此，拟议的研究将描述 EF2K 响应刺激而靶向 UPS 介导的降解的机制、EF2K 对蛋白质表达模式的具体调节，以及 EF2K 在可卡因运动敏化中的作用。这些研究将增进对基因特异性翻译模式和蛋白质合成和降解协调的作用的理解，以及滥用药物介导的可塑性机制，有可能促进新疗法的开发。 公共健康相关性：本提案的目标是描述可卡因介导的行为中基因特异性翻译控制和蛋白质合成和降解协调的功能、这些过程发生的机制以及它们对蛋白质表达模式的具体影响。人们认为成瘾背后的神经奖励回路的长期变化参与了这些分子过程，通过详细描述它们，可以开发出治疗成瘾的新方法。