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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

基本信息

批准号：
8694781
负责人：
Denise Marie Ferkey
金额：
$ 23.7万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8694781
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 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 public health relevance receptor receptor function research study

项目摘要

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）：多巴胺信号传导的缺陷与精神分裂症、药物成瘾、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式是通过信号蛋白的翻译后修饰。翻译后修饰是改变蛋白质合成后性质的共价加工事件，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。我们对小圆形线虫C. elegans已经揭示了PRMT在调节内源性多巴胺信号传导中的作用，并且我们使用人细胞培养物中的人D2多巴胺受体证实了这一发现。C.线虫是唯一一种已知整个神经系统（302个神经元）的发育谱系、物理位置和突触连接的生物。重要的是，C。秀丽线虫的行为受到许多影响人类神经系统功能的化学物质的调节，包括神经递质多巴胺。作为我们理解不同的调节机制如何协调调节G蛋白偶联信号传导的长期目标的重要一步，本申请的总体目标是具体确定精氨酸甲基化调节人D2 G蛋白偶联受体（GPCR）功能的机制。在这里，我们建议使用生物化学，蛋白质组学和细胞生物学的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结合、活化和通过腺苷酸环化酶的信号传导的影响，和（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新的调节G蛋白偶联信号转导的方法，从而有望导致识别新的治疗方法，以选择性地治疗与多巴胺信号失调相关的神经和精神疾病。