RGS2 regulation of D2 receptor signaling

RGS2 对 D2 受体信号传导的调节

基本信息

批准号：
9979825
负责人：
Rong Chen
金额：
$ 29.14万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9979825
关键词：
Address Agonist Amphetamines Animal Model Animals Autoreceptors Behavior Behavioral Binding Biochemical Biological Models Bioluminescence Brain Brain region Cell model Cells Confocal Microscopy Coupled Couples Data Dependovirus Disease Dominant-Negative Mutation Dopamine Dopamine D2 Receptor Drug Addiction Energy Transfer Future G Protein-Coupled Receptor Signaling GTP-Binding Proteins Genetic Goals Guanosine Triphosphate Homeostasis Hydrolysis Knowledge Length Link Maps Mediating Mental disorders Messenger RNA Midbrain structure Molecular N-terminal Neurobiology Neuroblastoma Pathology Pharmacology Physiological Play Predisposition Process Proteins Psychological reinforcement RGS Proteins RGS2 gene Rattus Receptor Activation Receptor Signaling Regulation Role Self Administration Signal Pathway Signal Transduction Signaling Protein Specificity Stimulus Surface Techniques Testing Time Ventral Tegmental Area Viral Vector addiction behavioral response dopaminergic neuron in vivo inhibitor/antagonist knock-down mutant nervous system disorder neuropsychiatric disorder new therapeutic target novel protein activation receptor receptor binding recruit response

项目摘要

Project Summary The overall goal of this project is to increase our understanding of neurobiological signaling process that mediates physiological and behavioral effects of dopamine. This proposal focuses on a novel regulation of dopamine D2 autoreceptor (D2AR) signaling in the midbrain by RGS2 (regulator of G protein signaling 2) proteins. Dysfunctional midbrain D2AR is implicated in neurological and psychiatric diseases. However, little knowledge is known about the mechanisms of midbrain D2AR signaling. D2R signals via its coupled Gαi/o protein to mediate cellular and behavioral responses to stimuli. The family of RGS proteins is a key negative modulator of D2R signaling by accelerating GTP hydrolysis and terminating G protein signaling. To date, no study has examined the associations between specific RGS proteins and D2AR signaling in midbrain dopaminergic neurons. We find that amphetamine self-administration increases RGS2 protein levels and decreases D2R-stimulated G protein activation in rat midbrain. Moreover, RGS2 and D2AR are both expressed in midbrain dopaminergic neurons. Thus, RGS2 and D2AR may be functionally linked. Using neuroblastoma N2A cells as a model system, we made a novel observation that RGS2 negatively regulates D2R-mediated Gαi/o signaling. Moreover, RGS2 couples with D2R via its N-terminus. Thus, we hypothesize that RGS2 directly interacts with D2R to engage a unique Gαi/o signaling pathway that controls physiological and behavioral responses of D2AR in midbrain dopaminergic neurons. This hypothesis will be tested in two specific aims: 1) assess whether RGS2 directly interacts with D2R to control D2R-mediated G protein signaling in N2A cells; and 2) determine the physiological and behavioral significance of the RGS2-D2AR interaction in dopaminergic neurons of ventral tegmental area. This proposal has a potential to identify RGS2 as a novel therapeutic target of the D2R signaling in vivo.

项目概要该项目的总体目标是增加我们对神经生物学信号传导过程的理解介导多巴胺的生理和行为效应。该提案重点关注多巴胺的新调节。 RGS2（G 蛋白信号传导调节器 2）在中脑中的多巴胺 D2 自身受体 (D2AR) 信号传导功能失调的中脑 D2AR 与神经和精神疾病有关，但影响很小。关于中脑 D2AR 信号通过其耦合的 Gαi/o 信号传导机制的了解。 RGS 蛋白家族是介导细胞和行为对刺激做出反应的关键蛋白。通过加速 GTP 水解和终止 G 蛋白信号传导来调节 D2R 信号传导迄今为止，还没有。研究检查了中脑中特定 RGS 蛋白和 D2AR 信号传导之间的关联我们发现苯丙胺自我给药会增加 RGS2 蛋白水平并减少大鼠中脑中 D2R 刺激的 G 蛋白激活此外，RGS2 和 D2AR 均表达。因此，RGS2 和 D2AR 可能在功能上与神经母细胞瘤相关。 N2A细胞作为模型系统，我们做了一个新的观察，即RGS2负向调节D2R介导的此外，RGS2 通过其 N 末端与 D2R 偶联，因此，我们与 RGS2 进行了斗争。直接与 D2R 相互作用，参与独特的 Gαi/o 信号通路，控制生理和 D2AR 在中脑多巴胺能神经元中的行为反应将在两个特定的中进行测试。目标：1) 评估 RGS2 是否直接与 D2R 相互作用以控制 N2A 中 D2R 介导的 G 蛋白信号传导细胞；2) 确定 RGS2-D2AR 相互作用的生理和行为意义腹侧被盖区的多巴胺能神经元有可能将 RGS2 识别为一种新型药物。体内 D2R 信号传导的治疗靶点。