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: 8220701
• 负责人: Shari Lenore Wiseman
• 金额: $ 3.52万
• 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 2013-01-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8220701
• 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; public health relevance; 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精确的时间和空间调节蛋白质水平，这在很大程度上是通过控制mRNA将mRNA转化为新蛋白质的转化以及通过泛素蛋白蛋白酶体系统（UPS）降解现有蛋白质的。使用蛋白质合成和UPS的药理抑制剂的研究表明，这些过程对于长期的突触可塑性和记忆巩固至关重要，这些过程的调节很可能与介导成瘾发展的脑奖励系统的可塑性有关。新兴的证据表明，长期可塑性的稳定需要基因特异性，而不是全球，翻译控制和协调或蛋白质合成和降解过程的平衡。发生这种情况的机制，蛋白质表达的特定变化以及这些过程对药物介导的行为的后果是该建议试图通过研究真核延长因子-2激酶的作用和调节来阐明的关键问题，Ca2，Ca2，一种CA2？伸长步骤。先前的研究和初步数据表明，EF2K既是基因特异性翻译的中心介体，又是蛋白质合成和降解的协调，尽管这些功能的机制和后果仍然待阐明。为此，拟议的研究将表征EF2K针对响应刺激的UPS介导的降解的机制，即EF2K对蛋白质表达的模式发挥作用的特定调节以及EF2K在cocains敏化中的作用。这些研究将提高人们对蛋白质合成和降解的转化和协调基因转化模式的作用，以及由滥用药物介导的可塑性机制，有可能使新疗法的发展。 公共卫生相关性：该提案的目的是表征可卡因介导的行为中蛋白质合成和降解的基因特异性转化控制的功能，这些过程发生的机制以及它们对蛋白质表达的模式的特定后果。基于成瘾基础的神经奖励电路的长期变化被认为可以参与这些分子过程，并且通过详细表征它们，可以开发出新的成瘾治疗方法。