Receptor trafficking profiles of clinically important dopaminergic drugs

描述（由申请人提供）：多巴胺能信号失调与几种不同的神经精神疾病有关，包括帕金森病（PD）、抑郁症、双相情感障碍、精神分裂症和成瘾。导致多巴胺信号改变的分子机制在很大程度上是未知的。多巴胺受体分为两类。d1样受体（D1R和D5R）是gs偶联的兴奋性gpcr， d2样受体（D2R、D3R和D4R）是gi偶联的抑制性gpcr。因此，这两类受体对神经传递有相反的作用，尽管所有这些受体的内源性配体都是多巴胺。据推测，在“正常”的大脑中，d1样受体和d2样受体的反应存在有效的平衡。然而，这种平衡在上述所有适应症的疾病状态中被破坏。事实上，在未经治疗的精神分裂症和双相情感障碍患者（1-3）、慢性抑郁症患者和接受左旋多巴和其他新一代多巴胺受体激动剂治疗的帕金森病患者（PD）中，D2Rs显著下调。在最近的工作中，我的小组发现，在多巴胺激动剂和内吞作用激活后，不同的多巴胺受体在循环内体和溶酶体之间被区分分类。具体来说，我们发现gs偶联的D1R在内吞作用后被循环利用，而gi偶联的D2R在内吞作用后在溶酶体中被降解。我们还发现了一种蛋白质，gpcr相关分选蛋白（GASP），我们认为它负责靶向几种gpcr，包括D2R，在内吞作用后降解。重要的是，我们发现一些治疗上重要的D2R激动剂促进D2R的内吞作用和下调，而D2R的拮抗剂阻止多巴胺介导的内吞作用和D2R的下调。基于这些研究，我们假设作用于D2R的激动剂药物（大多数PD药物）会急剧增强通过D2R的信号传导（从而取代与该疾病相关的多巴胺神经元的损失）。然而，在长期使用过程中，它们会导致D2R功能下调。因此，长期使用D2Rs后，D2Rs的选择性降解将有利于D1-Gs多巴胺能信号传导，这被认为是PD相关运动障碍的原因。此外，我们认为治疗相关的D2R拮抗剂可能通过促进D2R的上调/阻止D2R的下调来调节其作用。重要的是，虽然这些拮抗剂药物可以通过上调D2Rs来恢复平衡，但它们的有效性仍然有限，因为D2Rs在拮抗剂存在时不能有效地发出信号。在这里，我们将探讨多巴胺能配体对多巴胺受体运输的影响，目的是确定多巴胺受体激动剂，可以通过这些受体恢复音调，而不促进其下调。

DESCRIPTION (provided by applicant): Dysregulation of dopaminergic signaling is associated with several different neuropsychiatric diseases including Parkinson's disease (PD), depression, bipolar disorder, schizophrenia and addiction. The molecular mechanisms responsible for these alterations in dopamine signaling are largely unknown. There are two classes of dopamine receptor. D1-like receptors (D1R and D5R) are Gs-coupled excitatory GPCRs, while D2-like receptors (D2R, D3R and D4R) are Gi-coupled inhibitory GPCRs. Hence, these two receptor classes have opposing effects on neurotransmission, even though the endogenous ligand for all of these receptors is dopamine. Presumably, in a "normal" brain, there is an effective balance of D1-like and D2-like receptor responses. However, this balance becomes disrupted in the disease state for all the indications listed above. Indeed, D2Rs are significantly downregulated in untreated schizophrenic and bipolar patients (1-3), in patients with chronic depression and in patients with Parkinson's disease (PD) who have been treated with L-dopa and the other newer generation dopamine receptor agonist drugs. In recent work, my group has found that, following activation by dopamine agonist and endocytosis, distinct dopamine receptors are sorted differentially between recycling endosomes and lysosomes. Specifically, we found that the Gs-coupled D1R is recycled after undergoing endocytosis, while the Gi-coupled D2R is targeted for degradation in the lysosome after endocytosis. We also identified a protein, GPCR-associated sorting protein (GASP), which we believe is responsible for the targeting of several GPCRs, including the D2R, for degradation after endocytosis. Importantly, we found that some therapeutically important D2R agonists promote endocytosis and downregulation of D2Rs, while antagonist drugs at the D2R prevent dopamine-mediated endocytosis and downregulation of the D2R. Based on these studies, we hypothesize that agonist drugs that act at D2Rs (most of the PD drugs) would acutely enhance signaling through D2R (thereby substituting for the loss of dopamine neurons associated with this disease). However, during long-term use they would be expected to cause downregulation of D2R function. Selective degradation of D2Rs would, thereby, favor D1-Gs dopaminergic signaling after chronic use, which is thought to be responsible for dyskinesia associated with PD. In addition, we suggest that therapeutically relevant D2R antagonists may mediate their effects by facilitating upregulation/preventing downregulation of D2Rs. Importantly, while these antagonist drugs could restore the balance by upregulating D2Rs, their effectiveness would still be limited because D2Rs would not signal efficiently in the presence of the antagonist. Here, we will explore the effects of dopaminergic ligands on the trafficking of the dopamine receptors with the goal of identifying dopamine receptor agonists that can restore tone through these receptors without promoting their downregulation.