Dopamine Receptor Trafficking in Parkinson's Disease

描述（申请人提供）：抑制蛋白（ARR）和G蛋白偶联受体激酶（GRK）参与许多G蛋白偶联受体（包括多巴胺受体）的同源脱敏。脱敏的速度和程度与细胞内ARRs和GRKs的浓度和活性有关。反过来，ARR和GRK的量和活性可以通过受体刺激来调节。帕金森病（PD）中多巴胺的丢失导致运动缺陷，可能与纹状体多巴胺受体反应性的变化有关。用多巴胺前体L-DOPA进行多巴胺替代疗法，虽然一开始是成功的，但最终会导致运动并发症。帕金森病运动障碍和左旋多巴引起的副作用的分子机制仍然难以捉摸。多巴胺受体介导的信号转导通路的适应性与多巴胺能去神经和左旋多巴诱导的神经可塑性有关。多巴胺或左旋多巴治疗的损失产生行为反应的机制之一可能涉及受体脱敏机制的改变。我们假设，在PD和随后的非生理刺激L-DOPA治疗过程中，足够的多巴胺能刺激的损失导致在脱敏和多巴胺受体的运输的明显改变，可能是由于ARR和/或GRKs的表达的变化。具体而言，PD中多巴胺的损失可能会降低纹状体神经元中ARR/GRKs的浓度，从而导致多巴胺受体超敏。第一个具体的目的是检验这一假设，包括确定ARR/GRK的表达在纹状体的Pd患者和年龄匹配的控制在死后。在第二个目标中，将在PD大鼠模型中研究黑质纹状体损伤和L-DOPA治疗后ARR/GRK的表达。第三个目标集中在一种新的方式来调节黑质纹状体病变和L-DOPA治疗的行为和分子的后果，通过促进或抑制受体脱敏和贩运的可行性。为此，将使用慢病毒介导的GRK 2或其抑制剂基因转移到受损大鼠纹状体中。这些研究所产生的数据可能会开辟一个新的有前途的调查场所，最终导致新的策略管理PD。靶向受体脱敏机制的药物可能被证明对预防或减轻左旋多巴诱导的运动并发症特别有用。

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.