Dopamine Receptor Trafficking in Parkinson's Disease

描述(申请人提供)：阻滞素(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。脱敏的速度和程度与细胞内ARRs和GRKs的浓度和活性有关。反过来，ARRs和GRKs的数量和活性可以通过受体刺激来调节。帕金森氏病(PD)中多巴胺的丢失导致运动障碍，可能与纹状体多巴胺受体的反应性改变有关。多巴胺前体L-多巴的多巴胺替代疗法，虽然一开始成功，但最终会导致运动并发症。帕金森病患者运动障碍和L多巴所致副作用的分子机制仍不清楚。多巴胺受体介导的信号转导通路的适应性被认为与多巴胺能神经去神经和L多巴诱导的神经可塑性有关。失去多巴胺或L多巴治疗产生行为反应的机制之一可能涉及受体脱敏机制的修改。我们推测，帕金森病患者失去足够的多巴胺能刺激以及L多巴治疗期间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ARRs和/或GRKs表达的变化。具体地说，帕金森病患者多巴胺的丢失可能会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。为验证这一假设而设计的第一个特定目标包括在帕金森病患者和年龄匹配的对照组死后测定纹状体中ARR/GRK的表达。第二个目的是研究黑质纹状体损毁和L多巴治疗后ARR/GRK在帕金森病大鼠模型中的表达。第三个目标集中在通过促进或抑制受体脱敏和转运来调节黑质纹状体损害和L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或其抑制物基因转移到受损的大鼠纹状体。这些研究产生的数据可能会打开一个新的有希望的研究场所，最终导致PD管理的新策略。靶向受体脱敏机制的药物可能被证明对预防或减轻L-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.