Receptor trafficking profiles of clinically important dopaminergic drugs

临床上重要的多巴胺能药物的受体运输概况

• 批准号: 8433317
• 负责人: JENNIFER L WHISTLER
• 金额: $ 1.55万
• 依托单位: ERNEST GALLO CLINIC AND RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2013-07-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8433317
• 关键词: Adverse effects; Affinity; Agonist; Animal Model; Animals; Bipolar Disorder; Brain; Cells; Chronic; Coupled; DRD2 gene; Disease; Dopamine; Dopamine Agonists; Dopamine D1 Receptor; Dopamine D2 Receptor; Dopamine Receptor; Dopaminergic Agents; Down-Regulation; Drug Kinetics; Drug usage; Dyskinetic syndrome; Effectiveness; Endocytosis; Endosomes; Equilibrium; G Protein-Coupled Receptor Genes; G-Protein-Coupled Receptors; G-substrate; GTP-Binding Protein alpha Subunits, Gs; Generations; Goals; Golf; In Vitro; Inhibitory G-Protein Gi; Levodopa; Ligands; Lysosomes; Mediating; Mental Depression; Mental disorders; Modality; Molecular; Parkinson Disease; Patients; Pharmaceutical Preparations; Process; Proteins; Receptor Signaling; Recycling; Relative (related person); Schizophrenia; Signal Transduction; Sorting - Cell Movement; Up-Regulation; Work; addiction; base; chronic depression; clinically relevant; dopaminergic neuron; drug of abuse; neuropsychiatry; neurotransmission; novel; prevent; receptor; receptor coupling; response; trafficking

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.

描述（由申请人提供）：多巴胺能信号传导失调与包括帕金森氏病（PD），抑郁症，躁郁症，精神分裂症和成瘾在内的几种不同的神经精神疾病有关。导致多巴胺信号转变的分子机制在很大程度上未知。有两类的多巴胺受体。 D1样受体（D1R和D5R）是GS偶联的兴奋性GPCR，而D2样受体（D2R，D3R和D4R）是GI偶联的抑制GPCR。因此，尽管所有这些受体的内源性配体都是多巴胺，但这两个受体类别对神经传递的影响有相反的影响。据推测，在“正常”大脑中，D1样和D2样受体反应的有效平衡。但是，对于上面列出的所有适应症，这种平衡在疾病状态下都被破坏了。实际上，在未处理的精神分裂症和双极患者中，D2R显着下调（1-3），患有慢性抑郁症患者以及帕金森氏病（PD）患者（PD）接受了L-DOPA和其他其他新产生多巴胺受体受体激动剂药物的治疗。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，在回收内体和溶酶体之间将不同的多巴胺受体分类。具体而言，我们发现GS耦合的D1R在发生内吞作用后被回收，而GI偶联的D2R的靶向是在内吞作用后溶酶体降解。我们还鉴定了一种蛋白质，GPCR相关的分选蛋白（GASP），我们认为该蛋白质是靶向包括D2R在内的几种GPCR的靶向内吞作用后降解的。重要的是，我们发现某些具有治疗性的D2R激动剂会促进D2RS的内吞和下调，而D2R的拮抗剂药物可预防多巴胺介导的内吞作用和D2R的下调。基于这些研究，我们假设在D2RS（大多数PD药物）作用于D2R（大多数PD药物）的激动剂通过D2R急剧增强信号传导（从而取代了与该疾病相关的多巴胺神经元的丧失）。但是，在长期使用期间，预计它们会导致D2R功能的下调。 D2RS的选择性降解将在长期使用后有利于D1-GS多巴胺能信号传导，这被认为是导致与PD相关的运动障碍的原因。此外，我们建议与治疗相关的D2R拮抗剂可以通过促进/防止D2RS下调来介导其作用。重要的是，尽管这些拮抗剂可以通过上调D2R来恢复平衡，但它们的有效性仍然受到限制，因为在存在拮抗剂的情况下D2RS不会有效地信号。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，目的是鉴定可以通过这些受体恢复张力而无需促进其下调的多巴胺受体激动剂。