The A2AR-D2R heteromer as a potential target against Parkinson's disease

A2AR-D2R 异聚体作为对抗帕金森病的潜在靶点

基本信息

批准号：
8786348
负责人：
Candice Hatcher
金额：
$ 3.38万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8786348
关键词：
Adenosine Affect Agonist Animals Antiparkinson Agents Binding Biological Assay Cells Complex Corpus striatum structure Coupled DRD2 gene Data Development Disease Dissociation Dopamine Receptor Dorsal Drug Targeting Drug usage Ensure Exhibits G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors GTP-Binding Proteins Globus Pallidus Goals Guanine Nucleotides Guanosine Triphosphate In Vitro Incubated Individual Ipsilateral Lead Ligands Mediating Microdialysis Monitor Neurons Oocytes Parkinson Disease Pathology Patients Perfusion Pharmaceutical Preparations Pharmacology Physiological Play Property Protomer Rattus Receptor Activation Receptor Inhibition Receptor Signaling Reporter Role Signal Pathway Signal Transduction System Techniques Testing Therapeutic Therapeutic Human Experimentation Xenopus oocyte base clinical practice drug development gamma-Aminobutyric Acid in vivo innovation insight interest neuronal excitability neurotransmitter release new therapeutic target novel novel therapeutics public health relevance receptor research study therapeutic target

项目摘要

DESCRIPTION (provided by applicant): G protein-coupled receptors (GPCRs) are the targets of many drugs used in clinical practice because G proteins mediate a plethora of physiological functions. Recently, heteromeric GPCR complexes have become attractive targets in drug development since they exhibit distinct pharmacology and cell-specific localization from their respective protomers. Yet, the effect of heteromerization on the pharmacology and signaling of many GPCRs remains unknown. We have undertaken the task to examine the effect of heteromerization on the Gs signaling through the adenosine 2A receptor (A2AR) and Gi signaling through the dopamine receptor type 2 (D2R). Signaling through the A2AR-D2R heteromeric complex is of great interest as this heteromer is a potential pharmacological target for pathologies associated with dysfunctional dopaminergic signaling, such as Parkinson's disease. A2AR antagonists have been explored as therapeutics for Parkinson's disease because the A2AR allosterically inhibits signaling through the D2R. Therefore, we hypothesize that combining D2R full agonists with A2AR antagonists will maximize dopaminergic Gi signaling through the heteromer and will be more efficacious in treating Parkinson's disease than current therapeutics targeting just the D2R. To test this hypothesis, we have developed specific aims to characterize the potency and efficacy of various D2R and A2AR ligands on heteromeric signaling. In order to analyze A2AR-D2R heterocomplex cross signaling, we are using electrophysiological assays with heterologously expressed channels serving as reporters for GPCR signaling. Once we have characterized Gs and Gi signaling through the A2AR-D2R heteromer in our heterologous expression system, we will validate the results in native cells to ensure physiological relevance. To corroborate our findings, we will use in vitro [35S]GTP?S binding in primary neurons and in vivo microdialysis studies in rats. Characterization of the signaling pathway through the A2AR-D2R heteromer will provide insight into what ligands optimize dopaminergic signaling through the D2R leading to the development of novel therapeutics for Parkinson's disease.

描述（由申请人提供）：G蛋白偶联受体（GPCR）是临床实践中使用的许多药物的靶标，因为G蛋白介导多种生理功能。最近，异聚 GPCR 复合物已成为药物开发中有吸引力的目标，因为它们表现出与各自原体不同的药理学和细胞特异性定位。然而，异聚化对许多 GPCR 的药理学和信号传导的影响仍然未知。我们承担的任务是检查异聚化对通过腺苷 2A 受体 (A2AR) 的 Gs 信号传导和通过 2 型多巴胺受体 (D2R) 的 Gi 信号传导的影响。通过 A2AR-D2R 异聚体复合物的信号传导引起了人们的极大兴趣，因为这种异聚体是与多巴胺能信号传导功能障碍相关的病理学的潜在药理学靶点，例如帕金森病。 A2AR 拮抗剂已被探索作为帕金森病的治疗方法，因为 A2AR 变构抑制通过 D2R 的信号传导。因此，我们假设将D2R完全激动剂与A2AR拮抗剂相结合将通过异聚体最大化多巴胺能Gi信号传导，并且比目前仅针对D2R的疗法更有效地治疗帕金森病。为了检验这一假设，我们制定了具体目标来表征各种 D2R 和 A2AR 配体对异聚信号传导的效力和功效。为了分析 A2AR-D2R 异源复合物交叉信号传导，我们使用电生理学测定法，以异源表达通道作为 GPCR 信号传导的报告基因。一旦我们在异源表达系统中通过 A2AR-D2R 异聚体表征了 Gs 和 Gi 信号传导，我们将在天然细胞中验证结果以确保生理相关性。为了证实我们的发现，我们将使用原代神经元中的体外 [35S]GTP?S 结合和大鼠体内的微透析研究。通过 A2AR-D2R 异聚体的信号传导途径的表征将有助于深入了解哪些配体通过 D2R 优化多巴胺能信号传导，从而开发帕金森病的新疗法。