Dopamine D2 Receptor Mutations and Hyperkinetic Movement Disorders

多巴胺 D2 受体突变和多动性运动障碍

基本信息

批准号：
10640977
负责人：
KIM Arthur NEVE
金额：
--
依托单位：
PORTLAND VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10640977
关键词：
Adolescence Affect Agonist Arrestins Benign Binding Biological Brain Cells Cervical Dystonia Characteristics Chorea Clinical Cognitive deficits Cyclic AMP Cytoplasm DRD2 gene Data Dependence Disease Dopamine D2 Receptor Dopamine Receptor Dystonia Electrophysiology (science)Exhibits Exons Face Family Functional disorder G-Protein-Coupled Receptors GTP-Binding Proteins Gait abnormality Generations Genetic Polymorphism Goals Heterozygote Human Impairment Kinetics Knock-in Mouse Lead Learning Link Location Mediating Mental disorders Midbrain structure Modeling Motor Movement Movement Disorders Mus Mutation Neostriatum Neurologic Dysfunctions Neurologic Symptoms Outcome Parkinson Disease Pathogenicity Phosphorylation Phosphotransferases Positioning Attribute Potassium Channel Property RNA Splicing Receptor Activation Regulation Role Schizophrenia Severities Signal Transduction Single Nucleotide Polymorphism Slice Spasm Substance Use Disorder System Transmembrane Domain Variant Viral Work autosome clinical phenotype de novo mutation dopamine system dopaminergic neuron early onset genetic variant in silico in vivo inward rectifier potassium channel member molecular dynamics motor impairment mouse model mutant nervous system disorder neuroprotection neuropsychiatric symptom neuropsychiatry novel protein activation receptor receptor expression receptor function recruit societal costs therapeutic target

项目摘要

Project Summary Dopamine receptors are the primary therapeutic targets for a variety of neurological and psychiatric disorders, including schizophrenia, Parkinson’s disease, and many other movement disorders. The five subtypes of dopamine receptors (D1-D5) are members of the superfamily of G protein-coupled receptors. This proposal is focused on the D2 receptor and, in particular, on two novel DRD2 allelic variants that are linked to hyperkinetic movement disorders. An important distinction between the two variants is that subjects with the mutation M374R have more severe dysfunction with an earlier onset than those with the mutation I212F. The three aims will use a variety of approaches to compare and contrast the effects of the two mutations on D2 receptor function. Our overall goal is to determine which changes to receptor function are pathogenic, and which are benign or even potentially neuroprotective. D2-I212F exhibits increased constitutive activation of G proteins, increased sensitivity to low concentrations of agonist, decreased arrestin binding, slow kinetics for regulation of potassium channels, and inefficient expression. We will determine if the more severe clinical outcome caused by the M374R mutation is explained by qualitatively similar changes that differ only in magnitude, or if there are qualitative differences with I212F. In Aim 1 we will assess arrestin binding and G protein activation by the two novel variants, expanding our characterization to all D2 receptor-activated Gα subtypes and exploring the role of receptor phosphorylation. In Aim 2 we will carry out in silico studies of receptor activation. In Aim 3 we will create a knock-in mouse model of heterozygous expression of D2-M374R. We will evaluate the functional properties of D2-M374R in midbrain dopamine neurons by slice electrophysiology, using first viral expression of D2-M374R, and then the knock-in mice as they become available. We will also evaluate gait abnormalities in the knock-in mice, and quantify D2 receptor expression in midbrain and neostriatum. The aims proposed here will quantify the effect of these novel polymorphisms on the function and expression of the D2 receptor in cells and in mouse brain and should provide a biological explanation for manifestation of neurological dysfunction in humans with these variants.

项目摘要多巴胺受体是多种神经系统和精神疾病的主要治疗靶点，包括精神分裂症，帕金森氏病以及许多其他运动障碍。五个子类型多巴胺受体（D1-D5）是G蛋白偶联受体超家族的成员。该提议是专注于D2受体，尤其是在两个新型的DRD2等位基因变体上运动障碍。两种变体之间的一个重要区别是具有突变的受试者 M374R的功能障碍比突变I212F的发作更早。这三个目标将使用多种方法比较和对比两个突变对D2受体的影响功能。我们的总体目标是确定受体功能的哪些变化是致病性的，哪些是良性甚至可能具有神经保护性。 D2-I212F表现出增加的G蛋白的组成型激活，对低浓度激动剂的敏感性提高，降低阻滞蛋白结合，缓慢动力学调节钾通道和效率低下的表达。我们将确定是否引起更严重的临床结果通过M374R突变，仅在质量上相似的变化来解释，仅在大小上有所不同，或者有 I212F的定性差异。在AIM 1中，我们将评估两者的抑制蛋白结合和G蛋白激活新型变体，将我们的特征扩展到所有D2受体激活的Gα亚型并探索角色受体磷酸化。在AIM 2中，我们将在受体激活的计算机研究中进行。在目标3中，我们将创建D2-M374R的杂合表达的敲入小鼠模型。我们将评估功能 D2-M374R在中脑多巴胺神经元中通过SLICE电生理学的特性，使用第一病毒表达 D2-M374R，然后是敲入小鼠。我们还将评估步态异常这里提出的目的将量化这些新型多态性对D2受体在细胞中功能和表达的影响在小鼠大脑中，应提供一种生物学解释，以表现出神经功能障碍的表现这些变体的人。