Protein Arginine Methyltransferase Activity Modulates Dopaminergic Signaling

蛋白质精氨酸甲基转移酶活性调节多巴胺能信号传导

• 批准号: 8824970
• 负责人: Denise Marie Ferkey
• 金额: $ 19.75万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8824970
• 关键词: Activities of Daily Living; Adenylate Cyclase; Affect; Amino Acids; Arginine; Behavior; Biochemical; Biological; Brain; Caenorhabditis elegans; Cell Culture Techniques; Cells; Chemicals; Cognition; Complex; Coupled; Coupling; Cultured Cells; Cyclic AMP; Data; Defect; Development; Disease; Dopamine; Dopamine D2 Receptor; Dopamine Receptor; Drug Addiction; Event; Family; Foundations; Future; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; GTP-Binding Proteins; Goals; Health; Human; In Vitro; Knowledge; Lead; Learning; Left; Link; Mediating; Mental Depression; Mental disorders; Methylation; Modeling; Modification; Molecular; Motivation; Nematoda; Nervous System Physiology; Nervous system structure; Neurons; Neurotransmitters; Organism; Outcome; Parkinson Disease; Pathway interactions; Peptide Fragments; Pharmaceutical Preparations; Phosphorylation; Physiological; Positioning Attribute; Post-Translational Protein Processing; Process; Production; Property; Protein-Arginine N-Methyltransferase; Proteins; Proteomics; Regulation; Research; Rewards; Role; Schizophrenia; Sequence Homology; Signal Transduction; Signal Transduction Pathway; Signaling Protein; Staging; Structure; Synapses; Testing; Therapeutic; Wit; Work; adenylyl cyclase 1; adenylyl cyclase 2; base; in vivo; motor control; mutant; nervous system disorder; neuropsychiatry; novel therapeutic intervention; protein function; receptor; receptor function; research study

DESCRIPTION (provided by applicant): Defects in dopamine signaling have been linked to schizophrenia, drug addiction, depression and Parkinson's Disease. However, the incredible complexity of the human brain has left the physiological basis and molecular mechanisms underlying these complex diseases largely unknown. One way in which signal transduction pathways can be regulated is via the post-translational modification of signaling proteins. Post-translational modifications are covalent processing events that change the properties of a protein after its synthesis, such as its activity state, localization, turnover or interactions wit other proteins. Recently, methylation of the amino acid arginine (catalyzed by protein arginine methyltransferases/PRMTs) has begun to emerge as an important regulator of protein function. Our experiments in the small round worm (nematode) C. elegans have revealed a role for a PRMT in regulating endogenous dopamine signaling, and we corroborated this finding using the human D2 dopamine receptor in human cell culture. C. elegans is the only organism for which the developmental lineage, physical positions and synaptic connectivity of the entire nervous system (302 neurons) are known. Importantly, C. elegans behaviors are modulated by many of the same chemicals that affect human nervous system function, including the neurotransmitter dopamine. As an important step towards our long-term goal of understanding how diverse regulatory mechanisms coordinate to regulate G protein-coupled signaling, the overall objective of this application is to determine specifically the mechanism by which arginine methylation regulates human D2 G protein-coupled receptor (GPCR) function. Herein we propose to use biochemical, proteomic, and cell biological approaches to understand how arginine methylation regulates dopaminergic signal transduction. We will: (1) determine the effect of methylation on D2 - Galphai/o association, activation and signaling through adenylyl cyclase, and (2) identify methylated arginines in human D2 and establish their functional significance. Together, these studies will define a new means of regulating G protein-coupled signal transduction and thus are expected to lead to the identification of novel therapeutic approaches to selectively treat neurological and psychiatric disorders that are associated with dysregulation of dopamine signaling.

描述（由申请人提供）：多巴胺信号传导缺陷与精神分裂症、毒瘾、抑郁症和帕金森病有关。然而，人类大脑令人难以置信的复杂性使得这些复杂疾病背后的生理基础和分子机制在很大程度上未知。调节信号转导途径的一种方法是通过信号蛋白的翻译后修饰。翻译后修饰是共价加工事件，它改变蛋白质合成后的特性，例如其活性状态、定位、周转或与其他蛋白质的相互作用。最近，氨基酸精氨酸的甲基化（由蛋白质精氨酸甲基转移酶/PRMT 催化）已开始成为蛋白质功能的重要调节剂。我们对小圆虫（线虫）秀丽隐杆线虫的实验揭示了 PRMT 在调节内源性多巴胺信号传导中的作用，并且我们使用人类细胞培养物中的人类 D2 多巴胺受体证实了这一发现。线虫是唯一已知其整个神经系统（302 个神经元）的发育谱系、物理位置和突触连接的生物体。重要的是，线虫的行为受到许多影响人类神经系统功能的相同化学物质的调节，包括神经递质多巴胺。作为实现了解不同调控机制如何协调调节 G 蛋白偶联信号传导这一长期目标的重要一步，本申请的总体目标是明确精氨酸甲基化调节人类 D2 G 蛋白偶联受体 (GPCR) 功能的机制。在此，我们建议使用生物化学、蛋白质组学和细胞生物学方法来了解精氨酸甲基化如何调节多巴胺能信号转导。我们将：(1) 确定甲基化对 D2 - Galphai/o 关联、腺苷酸环化酶激活和信号传导的影响，以及 (2) 鉴定人 D2 中的甲基化精氨酸并确定其功能意义。总之，这些研究将定义一种调节 G 蛋白偶联信号转导的新方法，从而有望确定新的治疗方法，以选择性地治疗与多巴胺信号传导失调相关的神经和精神疾病。

项目成果

The protein arginine methyltransferase PRMT5 promotes D2-like dopamine receptor signaling.

• DOI: 10.1126/scisignal.aad0872
• 发表时间: 2015-11-10
• 期刊: Science signaling
• 影响因子: 7.3
• 作者: Likhite N;Jackson CA;Liang MS;Krzyzanowski MC;Lei P;Wood JF;Birkaya B;Michaels KL;Andreadis ST;Clark SD;Yu MC;Ferkey DM
• 通讯作者: Ferkey DM

The Protein Arginine Methyltransferase PRMT-5 Regulates SER-2 Tyramine Receptor-Mediated Behaviors in Caenorhabditis elegans.

• DOI: 10.1534/g3.118.200360
• 发表时间: 2018-07-02
• 期刊: G3 (Bethesda, Md.)
• 作者: Bowitch A;Michaels KL;Yu MC;Ferkey DM
• 通讯作者: Ferkey DM