Dopamine Receptor Trafficking in Parkinson's Disease

帕金森病中的多巴胺受体贩运

• 批准号: 6917329
• 负责人: Eugenia V Gurevich
• 金额: $ 32.28万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6917329
• 关键词: G protein coupled receptor kinase; Parkinson' s disease; RNase protection assay; abnormal involuntary movement; arrestins; brain disorder chemotherapy; corpus striatum; denervation; dopamine receptor; experimental brain lesion; gene therapy; human tissue; in situ hybridization; laboratory rat; levodopa; neuropathology; neuropeptides; neuropharmacology; nonhuman therapy evaluation; postmortem; protein quantitation /detection; receptor binding; receptor expression; receptor sensitivity; substantia nigra; western blottings

DESCRIPTION (provided by applicant): Arrestins (ARR) and G protein-coupled receptor kinases (GRK) participate in homologous desensitization of many G protein-coupled receptors including dopamine receptors. The rate and extent of desensitization is sensitive to the concentration and activity of ARRs and GRKs in the cells. In their turn, the amount and activity of ARRs and GRKs can be modulated by receptor stimulation. Loss of dopamine in Parkinson's disease (PD) causes motor deficits likely related to changes in responsiveness of striatal dopamine receptors. Dopamine replacement therapy with dopamine precursor L-DOPA, although successful at first, eventually leads to motor complications. Molecular mechanisms of motor disturbances in PD and of L-DOPA- induced side effects remain elusive. Adaptations in the signal transduction pathways mediated by dopamine receptors have been implicated an in neural plasticity induced by dopaminergic denervation and L-DOPA. One of the mechanisms by which loss of dopamine or L-DOPA treatment produce behavioral responses may involve modifications in the receptor desensitization machinery. We hypothesize that loss of adequate dopaminergic stimulation in PD and subsequent non-physiological stimulation during L-DOPA therapy lead to distinct alterations in desensitization and trafficking of dopamine receptors, possibly, due to changes in expression of ARRs and/or GRKs. Specifically, loss of dopamine in PD may reduce the concentration of ARRs/GRKs in striatal neurons, thereby leading to dopamine receptor supersensitivity. First specific aim designed to test this hypothesis includes determination of ARR/GRK expression in the striatum of Pd patients and age-matched controls at post-mortem. In the second aim, the ARR/GRK expression will be studied in the rat model of PD following nigrostriatal lesion and L-DOPA treatment. The third aim focuses on feasibility of a novel way to modulate behavioral and molecular consequences of the nigrostriatal lesion and L-DOPA treatment by facilitating or inhibiting receptor desensitization and trafficking. To that end, lentivirus-mediated gene transfer of GRK2 or its inhibitor into the lesioned rat striatum will be used. The data generated by these studies may open a new promising venue of investigation eventually leading to novel strategies for management of PD. Drugs targeting the receptor desensitization machinery may prove particularly useful for prevention or alleviating of L-DOPA-induced motor complications.

描述（由申请人提供）：阻止蛋白（ARR）和G蛋白偶联受体激酶（GRK）参与包括多巴胺受体在内的许多G蛋白偶联受体的同源脱敏。脱敏的速率和程度对细胞中ARR和GRK的浓度和活性敏感。反过来，可以通过受体刺激调节ARR和GRK的数量和活性。帕金森氏病（PD）中多巴胺的丧失导致运动缺陷可能与纹状体多巴胺受体反应性变化有关。多巴胺前体L-DOPA替代了多巴胺替代疗法，尽管最初是成功的，但最终导致运动并发症。 PD和L型诱导的副作用中运动障碍的分子机制仍然难以捉摸。由多巴胺受体介导的信号转导途径的适应已与多巴胺能神经膜和L-DOPA诱导的神经可塑性有关。多巴胺或L-DOPA处理丧失产生行为反应的机制之一可能涉及受体脱敏机制的修饰。我们假设在L-DOPA治疗期间，PD中充分多巴胺能刺激的丧失以及随后的非生理刺激导致多巴胺受体的脱敏和运输的明显改变，这可能是由于ARR和/或GRS表达的变化。具体而言，PD中多巴胺的丧失可能会降低纹状体神经元中ARR/GRK的浓度，从而导致多巴胺受体超敏。旨在检验此假设的第一个特定目的包括确定PD患者纹状体中ARR/GRK表达和验尸后的年龄匹配对照。在第二个目标中，将在黑质纹状体病变和L-DOPA处理后的大鼠模型中研究ARR/GRK表达。第三个目的是通过促进或抑制受体脱敏和运输来调节骨纹状体病变和L-DOPA处理的新型方法的可行性。为此，将使用慢病毒介导的GRK2或其抑制剂在病变的大鼠纹状体中的基因转移。这些研究产生的数据可能打开一个新的有希望的调查场所，最终导致了PD管理的新策略。靶向受体脱敏机制的药物可能证明对于预防或减轻L-DOPA诱导的运动并发症特别有用。