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：
10226196
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 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10226196
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身体和行为作用。该提议着重于对 RGS2（G蛋白信号2的调节剂2），多巴胺D2自身受体（D2AR）信号传导蛋白质。中脑功能失调D2AR在神经和精神病疾病中暗示。但是，很少知识了解中脑D2AR信号传导的机制。 D2R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蛋白质家族是关键的负面通过加速GTP水解和终止G蛋白信号传导的D2R信号调节剂。迄今为止，没有研究检查了中脑的特定RGS蛋白与D2AR信号的关联多巴胺能神经元。我们发现，苯丙胺自我给药增加了RGS2蛋白水平，并且减少大鼠中脑中D2R刺激的G蛋白激活。而且，RGS2和D2AR均表达在中脑多巴胺能神经元中。这是RGS2和D2AR的功能链接。使用神经母细胞瘤 N2A细胞作为模型系统，我们进行了一种新颖的观察结果，RGS2对D2R介导的负调控 GαI/O信号传导。此外，与D2R的RGS2夫妇通过其N末端。那我们假设RGS2 直接与D2R相互作用以参与控制生理和中脑多巴胺能神经元中D2AR的行为反应。该假设将在两个特定的目的：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相互作用的物理和行为意义腹侧对段区域的多巴胺能神经元。该建议有可能识别RGS2作为新颖的 D2R信号在体内的治疗靶标。