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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.

项目摘要这个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。该提案的重点是一种新的监管，多巴胺D2自身受体（D2 AR）通过RGS 2（G蛋白信号传导调节因子2）在中脑中的信号传导 proteins.中脑D2 AR功能障碍与神经和精神疾病有关。不过小关于中脑D2 AR信号传导的机制的知识是已知的。D2 R信号通过其耦合的Gαi/o 蛋白质介导细胞和行为对刺激的反应。RGS蛋白家族是一个关键的阴性通过加速GTP水解和终止G蛋白信号传导来调节D2 R信号传导。至今没有一项研究检测了中脑中特异性RGS蛋白和D2 AR信号之间的关系，多巴胺能神经元我们发现，安非他明自我管理增加RGS 2蛋白水平，降低大鼠中脑中D2 R刺激的G蛋白活化。此外，RGS 2和D2 AR均表达于中脑多巴胺能神经元中。因此，RGS 2和D2 AR可以在功能上连接。利用神经母细胞瘤 N2 A细胞作为模型系统，我们进行了一个新的观察，RGS 2负调控D2 R介导的 Gαi/o信号。此外，RGS 2通过其N-末端与D2 R偶联。因此，我们假设RGS 2 直接与D2 R相互作用，参与独特的Gαi/o信号通路，控制生理和中脑多巴胺能神经元中D2 AR的行为反应。这一假设将在两个具体的目的：1）评估RGS 2是否直接与D2 R相互作用以控制N2 A中D2 R介导的G蛋白信号传导细胞;和2）确定RGS 2-D2 AR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。这一建议有可能确定RGS 2作为一种新的在体内D2 R信号传导的治疗靶点。