Proteomic and Transcriptional Analysis of Cilia-Dependent Dopamine Receptor 1 Signaling

纤毛依赖性多巴胺受体 1 信号传导的蛋白质组学和转录分析

• 批准号: 10017361
• 负责人: KIRK A MYKYTYN
• 金额: $ 19.5万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-12 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10017361
• 关键词: Adult; Agonist; Anxiety Disorders; Bardet-Biedl Syndrome; Behavioral; Brain; Brain region; Cilia; Cognitive deficits; Complement; Congenital neurologic anomalies; Corpus striatum structure; Cues; Cyclic AMP; Defect; Development; Disease; Dopamine Receptor; Drug Addiction; Environment; Event; Foundations; Functional disorder; Future; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; Genes; Genetic Diseases; Genetic Transcription; Goals; Homeostasis; Human body; Individual; Label; Link; Malignant Neoplasms; Membrane; Methods; Molecular; Motor Activity; Movement Disorders; Mus; Mutate; Neurologic; Neurons; Obesity; Organelles; Outcome; Pathway interactions; Physiological; Process; Proteins; Proteomics; Receptor Signaling; Role; Sensory; Signal Pathway; Signal Transduction; Signaling Protein; Testing; Therapeutic; Therapeutic Agents; Treatment Efficacy; Work; appendage; cell type; ciliopathy; experimental study; human disease; innovation; insight; nervous system disorder; new therapeutic target; novel; prevent; public health relevance; response; social deficits; therapeutic target; trafficking; transcriptome sequencing; transcriptomics

ABSTRACT Modulation of dopaminergic signaling has therapeutic potential for numerous neurological conditions, including movement disorders, drug addiction, and anxiety disorders. One promising approach for modulation of dopaminergic pathways involves targeting specific dopamine receptors to differentially regulate individual signaling pathways. Yet, significant gaps in our understanding of dopamine receptor signaling remain and hinder such efforts. We have discovered that dopamine receptor 1 (D1) dynamically localizes to primary cilia on neurons in several brain regions, including the striatum. Primary cilia are cellular appendages that provide critical sensory and signaling functions. Numerous human diseases are now known to be caused by defects in primary cilia. Remarkably, we still know very little about how primary cilia impact neuronal function, despite the fact that most, if not all, central neurons in the mammalian brain possess a primary cilium. Primary cilia are restricted compartments and select G protein-coupled receptors (GPCRs), such as D1, are targeted to the ciliary membrane in neurons. Downstream effectors of GPCR signaling also localize to neuronal cilia, suggesting that primary cilia support specialized non-synaptic dopaminergic signaling. Indeed, we have discovered that disrupting cilia in D1-expressing neurons results in deficient D1 signaling, as well as reduced basal locomotor activity and obesity. In this proposal we will use cutting-edge approaches to identify the molecular mechanisms underlying the role of cilia in D1-expressing neurons and provide critical insight into the importance of cilia in D1 signaling. The outcomes of this work will fundamentally advance our understanding of D1 signaling in the striatum and may implicate cilia-specific factors as novel targets for therapeutics.

摘要 多巴胺能信号传导的调节对许多神经系统疾病具有治疗潜力，包括 运动障碍、药物成瘾和焦虑症。一种有前途的方法用于调节 多巴胺能通路涉及靶向特异性多巴胺受体，以差异调节个体的多巴胺能。 信号通路然而，我们对多巴胺受体信号传导的理解仍然存在重大差距， 阻碍这种努力。我们已经发现多巴胺受体1（D1）动态定位于初级纤毛 包括纹状体在内的几个大脑区域的神经元上。初级纤毛是细胞的附属物， 关键的感觉和信号功能。现在已知许多人类疾病是由以下缺陷引起的： 初级纤毛值得注意的是，我们仍然对初级纤毛如何影响神经元功能知之甚少， 事实上，哺乳动物大脑中的大多数（如果不是全部的话）中枢神经元都具有初级纤毛。初级纤毛 限制性区室和选择G蛋白偶联受体（GPCR），如D1，靶向 神经元中的纤毛膜。GPCR信号传导的下游效应物也定位于神经元纤毛， 提示初级纤毛支持专门的非突触多巴胺能信号传导。我确已 发现破坏表达D1的神经元中的纤毛会导致D1信号传导不足， 基础运动能力和肥胖。在本提案中，我们将使用最先进的方法来确定 纤毛在表达D1的神经元中的作用的分子机制，并提供关键的洞察力， 纤毛在D1信号传导中的重要性这项工作的成果将从根本上促进我们对 纹状体中的D1信号传导，可能涉及纤毛特异性因子作为治疗的新靶点。