Dopamine Receptor Trafficking in Parkinson's Disease

描述（由申请人提供）：Arrestins （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。细胞中ARRs和GRKs的浓度和活性对脱敏的速度和程度非常敏感。反过来，arr和grk的数量和活性可以通过受体刺激来调节。帕金森病（PD）中多巴胺的缺失导致运动缺陷，可能与纹状体多巴胺受体的反应性变化有关。多巴胺前体左旋多巴的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。PD患者运动障碍的分子机制和左旋多巴诱导的副作用仍不清楚。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支配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缺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。我们推测，在左左多巴治疗期间，PD患者缺乏足够的多巴胺能刺激和随后的非生理性刺激导致多巴胺受体脱敏和转运的明显改变，可能是由于arr和/或GRKs表达的改变。具体来说，PD中多巴胺的缺失可能降低纹状体神经元中ARRs/GRKs的浓度，从而导致多巴胺受体超敏感。为验证这一假设而设计的第一个特定目标包括在Pd患者和年龄匹配的对照者死后测定纹状体中ARR/GRK的表达。第二个目的是研究黑质纹状体损伤和左旋多巴治疗后PD大鼠模型中ARR/GRK的表达。第三个目标侧重于通过促进或抑制受体脱敏和转运来调节黑质纹状体病变和左旋多巴治疗的行为和分子后果的新方法的可行性。为此，将使用慢病毒介导的GRK2或其抑制剂基因转移到受损大鼠纹状体中。这些研究产生的数据可能会打开一个新的有希望的研究领域，最终导致PD治疗的新策略。靶向受体脱敏机制的药物可能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.