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

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目及 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 中心，但不一定是研究者所在的机构。 该子项目将研究纹状体特异性蛋白RGS 9 -2的功能，RGS 9 -2是G α GT3加速蛋白RGS家族的成员。 我们先前的数据表明RGS 9 -2在L-DOPA诱导的运动障碍（LID）和迟发性运动障碍（TD）的发展中是关键的。 LID和TD分别是帕金森病和精神病药物治疗的不可逆神经运动毒性。虽然病因不明，我们提出了一个初步的分子模型：D2-多巴胺受体（D2 R）是抗精神病药物和左旋多巴的主要靶点。 RGS 9 -2通过RGS 9 DEP结构域靶向D2 DR，并在纹状体神经元中功能性区室化D2 R，以阻断D2 DR介导的NMDA受体和Ca 2+通道抑制。 延长的药物治疗产生代偿性改变，破坏RGS 9 -2介导的细胞区室化。 这些代偿反应导致异常的基底神经节信号处理和药物诱导的异常不自主运动。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。 通过更好地理解RGS 9 -2调节D2 R反应的机制，也将加强这一努力。 作为RGS家族的一员，RGS 9 -2可以加速D2 R反应的失活动力学，正如我们和其他人已经证明的那样。 然而，尚不清楚加速G蛋白周转是否是RGS 9 -2调节GPCR信号转导机制的唯一机制。 因此，我们将研究RGS 9 -2对D2 R的多种信号转导机制的影响，包括激动剂依赖性内化和D2 R活化丝裂原活化蛋白激酶（MAPK）途径。 虽然目前的建议仅限于表征RGS 9 -2的细胞功能，但我希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。最后，我们已经确定了RGS 9基因的多个多态性，这些多态性在精神分裂症和帕金森病患者中富集。 我们建议调查这些多态性对RGS 9功能和表达的影响。

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 alpha 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 preliminary molecular model: D2-dopamine receptors (D2R) are a major target of both antipsychotic drugs and L-DOPA. RGS9-2 targets to D2DR via the RGS9 DEP domain and functionally compartmentalizes D2R in striatal neurons to block D2DR-mediated inhibition of NMDA receptors and Ca2+ channels. Prolonged drug-treatment produces compensatory alterations that disrupt RGS9-2 mediated 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. This effort will also be enhanced by a better understanding of the mechanisms by which RGS9-2 can modulate D2R responses. As a member of the RGS family, RGS9-2 can accelerate the deactivation kinetics of D2R responses, as we and others have demonstrated. It is unclear, however; if accelerating G protein turnover is the only mechanism by which RGS9-2 can modulate GPCR signal transduction mechanisms. Thus we will examine the effect of RGS9-2 on multiple signal transduction mechanisms of D2R including agonist dependent internalization and D2R activation the Mitogen Activated Protein Kinase (MAPK) pathways. 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. Finally, we have identified multiple polymorphisms in the RGS9 gene that are enriched in schizophrenic and Parkinson's patients. We propose investigations of the effect of these polymorphisms on RGS9 function and expression.