MODULATION OF D2-LIKE DOPAMINE RECEPTOR-MEDIATED STRIATAL SIGNALING PATHWAYS BY

D2 样多巴胺受体介导的纹状体信号通路的调节

• 批准号: 7609982
• 负责人: Abraham Kovoor
• 金额: $ 9.88万
• 依托单位: UNIVERSITY OF RHODE ISLAND
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7609982
• 关键词: Antipsychotic Agents; Basal Ganglia; Binding; Cell physiology; Computer Retrieval of Information on Scientific Projects Database; Corpus striatum structure; Coupling; Data; Development; Dopamine D2 Receptor; Dopamine Receptor; Dyskinetic syndrome; Family; Funding; Glutamate Receptor; Grant; Guanosine Triphosphate Phosphohydrolases; In Vitro; Institution; Maps; Mediating; Modeling; Modification; Molecular; Motor; Movement; N-Methyl-D-Aspartate Receptors; Neurologic; Neurons; Parkinson Disease; Pharmaceutical Preparations; Pharmacotherapy; Phosphorylation; Proteins; Psychotic Disorders; Research; Research Personnel; Resources; Role; Signal Pathway; Signal Transduction; Source; Surface; Tardive Dyskinesia; Testing; Toxic effect; United States National Institutes of Health; abnormal involuntary movement; expectation; member; receptor coupling; reconstitution; tool; voltage

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. RGS9-2 is a member of the RGS family of G¿ GTPase accelerating proteins that is expressed specifically in the striatum, an important component of the basal ganglia loop that controls movement. Our recent data suggest that RGS9 2 is critical in the development of L-DOPA induced dyskinesia (LID) and tardive dyskinesia (TD), the devastating and irreversible neurological motor toxicities of the pharmacotherapy of Parkinson's disease and psychoses, respectively. Our data suggests a preliminary model for TD and LID: RGS9-2 targets to D2-like dopamine receptors (D2-like DR) via the RGS9 DEP domain and compartmentalizes D2-like DR in striatal neurons to block D2-like DR-mediated inhibition of NMDA-type glutamate receptors and voltage-activated Ca2+ channels. Prolonged drug-treatment (antipsychotic drugs or L-DOPA) produces alterations in the function of RGS9-2 that disrupt compartmentalization leading to abnormal basal ganglia signaling and to abnormal involuntary movements. Determining how such compartmentalization is disrupted will require a better understanding of the D2DR-RGS9-2 interaction which has been suggested by our colocalization studies. Hence we will determine if the targeting of RGS9-2 to D2 dopamine receptors (D2DR) involves either a direct or indirect physical interaction. We will map and characterize the interacting surfaces and evaluate the effect of covalent modifications such as protein phosphorylation on the molecular interaction. We will in addition investigate the molecular mechanism for abnormal signaling between D2-like DR and NMDA-receptors observed in the absence of RGS9. We will test the hypothesis that coexpressed RGS9-2 can inhibit D2DR-NMDA-receptor coupling reconstituted in vitro. Parallel approaches will examine the role for RGS9-2 in the coupling between striatal D2DR and voltage-activated Ca2+ channels. Though the present proposal is restricted to characterizing the cellular function of RGS9-2 it is my expectation that the effort will provide us with the tools to test, validate and expand our preliminary model for LID and TD, in subsequent studies.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 RGS 9 -2是GT3加速蛋白的RGS家族的成员，其在纹状体中特异性表达，纹状体是控制运动的基底神经节环的重要组成部分。 我们最近的数据表明，RGS 9 2在L-DOPA诱导的运动障碍（LID）和迟发性运动障碍（TD）的发展中是至关重要的，L-DOPA诱导的运动障碍（LID）和迟发性运动障碍（TD）分别是帕金森病和精神病药物治疗的破坏性和不可逆的神经运动毒性。 我们的数据表明TD和LID的初步模型：RGS 9 -2通过RGS 9 DEP结构域靶向D2样多巴胺受体（D2样DR），并在纹状体神经元中区室化D2样DR，以阻断D2样DR介导的NMDA型谷氨酸受体和电压激活的Ca 2+通道抑制。 长期药物治疗（抗精神病药物或L-DOPA）会导致RGS 9 -2功能改变，从而破坏区室化，导致基底神经节信号异常和不自主运动异常。 确定这种区室化是如何被破坏的将需要更好地理解D2 DR-RGS 9 -2相互作用，这已经由我们的共定位研究提出。 因此，我们将确定RGS 9 -2靶向D2多巴胺受体（D2 DR）是否涉及直接或间接的物理相互作用。 我们将绘制和表征相互作用表面，并评估共价修饰（如蛋白质磷酸化）对分子相互作用的影响。 此外，我们还将研究在RGS 9不存在的情况下观察到的D2样DR和NMDA受体之间异常信号传导的分子机制。 我们将检验共表达的RGS 9 -2可以抑制体外重建的D2 DR-NMDA-受体偶联的假设。 平行方法将检查RGS 9 -2在纹状体D2 DR和电压激活的Ca 2+通道之间的偶联中的作用。 虽然目前的提议仅限于表征RGS 9 -2的细胞功能，但我期望这项工作将为我们提供工具，以在后续研究中测试，验证和扩展我们对LID和TD的初步模型。