RGS2 对 D2 受体信号传导的调节-猫眼课题宝

RGS2 对 D2 受体信号传导的调节

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

项目状态：

已结题

起止时间：

2017-09-01 至 2022-07-31

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

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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.

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