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：
9899536
负责人：
Rong Chen
金额：
$ 3.27万
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 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9899536
关键词：
Address Agonist Amphetamines Animal Model Animals Autoreceptors Behavior Behavioral Binding Biochemical Biological Models Bioluminescence Brain Brain region Cell Line Cell model Cells Confocal Microscopy Coupled Couples Data Dependovirus Disease Dominant-Negative Mutation Dopamine Dopamine D2 Receptor Drug abuse Energy Transfer Future G Protein-Coupled Receptor Signaling GTP-Binding Proteins Gene Expression Gene Proteins Genetic Goals Guanosine Triphosphate Homeostasis Hydrolysis Knowledge Length Link Mammalian Cell Maps Mediating Mental disorders Messenger RNA Midbrain structure Molecular N-terminal Neurobiology Neuroblastoma Neurons Parkinson Disease Pathology Pharmacologic Substance Pharmacology Physiological Physiology Play Predisposition Process Proteins Psychological reinforcement RGS Proteins RGS2 gene Rattus Receptor Activation Receptor Signaling Regulation Role Schizophrenia Self Administration Signal Pathway Signal Transduction Signaling Protein Specificity Stimulus Surface System Techniques Testing Time Ventral Tegmental Area addiction behavioral response dopaminergic neuron improved in vivo inhibitor/antagonist knock-down mutant nervous system disorder neuropsychiatric disorder novel protein activation receptor receptor binding recruit response

Address Agonist Amphetamines Animal Model Animals Autoreceptors Behavior Behavioral Binding Biochemical Biological Models Bioluminescence Brain Brain region Cell Line Cell model Cells Confocal Microscopy Coupled Couples Data Dependovirus Disease Dominant-Negative Mutation Dopamine Dopamine D2 Receptor Drug abuse Energy Transfer Future G Protein-Coupled Receptor Signaling GTP-Binding Proteins Gene Expression Gene Proteins Genetic Goals Guanosine Triphosphate Homeostasis Hydrolysis Knowledge Length Link Mammalian Cell Maps Mediating Mental disorders Messenger RNA Midbrain structure Molecular N-terminal Neurobiology Neuroblastoma Neurons Parkinson Disease Pathology Pharmacologic Substance Pharmacology Physiological Physiology Play Predisposition Process Proteins Psychological reinforcement RGS Proteins RGS2 gene Rattus Receptor Activation Receptor Signaling Regulation Role Schizophrenia Self Administration Signal Pathway Signal Transduction Signaling Protein Specificity Stimulus Surface System Techniques Testing Time Ventral Tegmental Area addiction behavioral response dopaminergic neuron improved in vivo inhibitor/antagonist knock-down mutant nervous system disorder neuropsychiatric disorder novel protein activation receptor receptor binding recruit response

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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 receptor (D2R) signaling in the midbrain by RGS2 (regulator of G protein signaling 2) protein. Dysfunctional midbrain D2R is implicated in neurological and psychiatric diseases. However, little knowledge is known about the mechanisms of midbrain D2R signaling. This proposal will delineate the mechanistic actions of RGS2 on D2R signaling and interrogate RGS2 in dopaminergic neurons as a critical modulator of midbrain D2R-mediated dopamine physiology and behavior. 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 D2R 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 somatodendritic D2R are both expressed in midbrain dopaminergic neurons. Thus, RGS2 and D2R may be functionally linked which has never been examined in a neuronal system. Using neuroblastoma N2A cells as a model system, we made the 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 D2R 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 neuron-like cell lines; and 2) determine the physiological and behavioral significance of the RGS2-D2R interaction in dopaminergic neurons of ventral tegmental area. This proposal may expand the repertoire and diversity of D2R regulation and has a potential to identify RGS2 as a novel component of the D2R signaling network 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）蛋白质中脑中的多巴胺D2受体（D2R）信号传导。中脑功能失调D2R在神经和精神病疾病中隐含。但是，知识很少了解中脑D2R信号的机制。该建议将描述机制 RGS2对D2R信号传导和询问多巴胺能神经元中的RGS2的作用中脑D2R介导的多巴胺生理和行为。 D2R信号通过其耦合的GαI/O蛋白介导细胞和行为对刺激的反应。家庭 RGS蛋白是通过加速GTP水解并终止G的D2R信号传导的关键负调节器蛋白质信号传导。迄今为止，尚未研究特定RGS蛋白与D2R之间的关联中脑多巴胺能神经元的信号传导。我们发现苯丙胺自我给药增加了RGS2 蛋白质水平并降低了大鼠中脑中D2R刺激的G蛋白激活。此外，RGS2和 somatendritic D2R均在中脑多巴胺能神经元中表达。那是RGS2和D2R 在功能上链接，从未在神经元系统中进行检查。使用神经母细胞瘤N2A细胞作为A 模型系统，我们进行了新的观察结果，即RGS2负调节D2R介导的GαI/O信号传导。此外，与D2R的RGS2夫妇通过其N末端。这，我们假设RGS2直接与 D2R参与独特的GαI/O信号传导途径，该途径控制D2R的物理和行为响应在中脑多巴胺能神经元中。该假设将以两个具体目的进行检验：1）评估是否是否 RGS2直接与D2R相互作用，以控制D2R介导的G蛋白信号传导在神经元样细胞系中；和2）确定多巴胺能神经元中RGS2-D2R相互作用的身体和行为意义腹侧对段区域。该建议可能会扩大D2R法规的曲目和多样性，并具有在体内识别RGS2作为D2R信号网络的新组件的潜力