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: 7725160
• 负责人: Abraham Kovoor
• 金额: $ 18.66万
• 依托单位: UNIVERSITY OF RHODE ISLAND
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7725160
• 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; Etiology; Family; Funding; Grant; Guanosine Triphosphate Phosphohydrolases; In Vitro; Institution; Lead; Maps; Mediating; Modeling; Modification; Molecular; Motor; N-Methyl-D-Aspartate Receptors; Neurologic; Neurons; Parkinson Disease; Pharmaceutical Preparations; Pharmacotherapy; Phosphorylation; Proteins; Psychotic Disorders; RGS9 protein; 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; computerized data processing; expectation; member; molecular modeling; receptor coupling; reconstitution; response; 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. This subproject will investigate the functions of a striatal specific protein, RGS9-2, a member of the RGS family of G¿ GTPase accelerating proteins. Our previous data suggest that RGS9-2 is critical in the development of L-DOPA induced dyskinesia (LID) and tardive dyskinesia (TD). LID and TD are irreversible neurological motor toxicities of the pharmacotherapy of Parkinson's disease and psychotic disorders, respectively. While the etiology is unknown we have proposed a prelimainary molecular model: D2-dopamine receptors (D2DR) are a major target of both antipsychotic drugs and L-DOPA. RGS9-2 targets to D2DR via the RGS9 DEP domain and functionally compartmentalizes D2DR in striatal neurons to block D2DR-mediated inhibition of NMDA receptors and Ca2+ channels. Prolonged drug-treatment produces compensatory alterations that disrupt RGS9-2mediated cellular compartmentalization. These compensatory responses, lead to abnormal basal ganglia signal processing and to drug-induced 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 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 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.

该副本是使用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这是调查员的机构。 该主题项目将研究纹状体特异性蛋白RGS9-2的功能，RGS9-2是GTPase加速蛋白的RGS家族的成员。我们以前的数据表明，RGS9-2对于L-DOPA诱导运动障碍（LID）和迟发性运动障碍（TD）的发展至关重要。盖子和TD分别是帕金森氏病和精神病药物治疗的不可逆性神经运动毒性。虽然病因尚不清楚，但我们提出了一个初步分子模型：D2-多巴胺受体（D2DR）是抗精神病药和L-DOPA的主要目标。 RGS9-2通过RGS9 DEP结构域靶向D2DR，并在功能上划分纹状体神经元中的D2DR，以阻止D2DR介导的NMDA受体和Ca2+通道的抑制。长时间的药物治疗会产生补偿性改变，破坏RGS9-介导的细胞分区化。这些补偿性反应导致基底神经节信号处理异常，并导致药物引起的异常非自愿运动。确定如何破坏这种隔室化将需要更好地理解D2DR-RGS9-2相互作用，这是我们的共定位研究所建议的。因此，我们将确定RGS9-2至D2DR的靶向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的表面，并评估共价修饰（例如蛋白质磷酸化对分子相互作用）的影响。另外，我们将研究在没有RGS9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。我们将检验以下假设：共表达的RGS9-2可以抑制在体外重构的D2DR-NMDA受体耦合。平行方法将检查RGS9-2在纹状体D2DR和电压激活的Ca2+通道之间的耦合中的作用。尽管目前的提案限制了RGS9-2的细胞功能的限制，但我期望在随后的研究中，努力将为我们提供测试，验证和扩展我们针对盖子和TD的初步模型的工具。