Neuronal primary cilia in dopamine receptor 1 signaling

多巴胺受体 1 信号传导中的神经元初级纤毛

• 批准号: 8970202
• 负责人: KIRK A MYKYTYN
• 金额: $ 23.1万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8970202
• 关键词: Adenylate Cyclase; Adult; Affect; Agonist; Alleles; Amygdaloid structure; Anosmia; Bardet-Biedl Syndrome; Behavioral; Biochemical; Biological Assay; Brain; Cilia; Clinical; Congenital neurologic anomalies; Corpus striatum structure; Cues; Cyclic AMP; Cystic Kidney Diseases; Defect; Dopamine Receptor; Foundations; Functional disorder; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; Goals; Hereditary Disease; Homeostasis; Human; Human body; Hypogonadism; Intellectual functioning disability; Lead; Link; Maintenance; Malignant Neoplasms; Mammalian Cell; Motor Activity; Mus; Neuraxis; Neuromodulator; Neurons; Obesity; Organelles; Organogenesis; Outcome; Phenotype; Photoreceptors; Physiological; Play; Proteins; Receptor Signaling; Regulation; Retinal Degeneration; Role; Sensory; Signal Transduction; Signaling Protein; Social Problems; Testing; Work; appendage; base; cell type; ciliopathy; human disease; insight; mouse model; nervous system disorder; promoter; public health relevance; recombinase; research study; response; serotonin 6 receptor; skeletal; somatostatin receptor 3; trafficking

 DESCRIPTION (provided by applicant): Primary cilia are typically solitary, immotile cellular appendages that project from nearly all mammalian cell types. They provide important sensory and signaling functions and defects in the formation or function of primary cilia leads to a class of human diseases called ciliopathies. Due to the ubiquity of primary cilia, ciliopathies are associated with a wide range of clinical features, including cystic kidney disease, retinal degeneration, obesity, skeletal defects, hypogonadism, anosmia, behavioral disturbances, social deficits and intellectual disability. The range of neurological disorders associated with ciliopathies indicates that cilia play important roles in the brain. In fact, most neurons throughot the mammalian brain possess a primary cilium that is enriched for specific G protein-coupled receptors (GPCRs), such as dopamine receptor 1 (D1). It is thought that neuronal cilia sense neuromodulators and provide specialized signaling. Yet, the roles of primary cilia in neuronal function remain largely unknown. We have discovered that trafficking of GPCRs to and from neuronal cilia is dynamic and regulation of GPCR ciliary localization is disrupted in mouse models of the human ciliopathy Bardet-Biedl syndrome (BBS). For example, D1 shows abnormal accumulation in cilia on striatal and amygdala neurons in BBS mice. Interestingly, these mice display reduced locomotor activity and adult onset obesity; phenotypes that are consistent with defective D1 signaling. We hypothesize that trafficking of GPCRs into and out of cilia coordinates receptor signaling and disruption of ciliary localization alters the regulation o GPCR signaling. The objectives of this application are to determine the effects of D1 ciliary accumulation and loss of D1 ciliary localization on D1 expression, trafficking and signaling. The outcomes of this work are expected to fundamentally advance our understanding of the role of cilia in the regulation of D1 signaling. These studies will provide the critical insights into ciliry signaling that are needed to establish the importance of GPCR localization in neuronal cilia throughout the brain.

 描述（由申请人提供）：初级纤毛通常是孤立的、不动的细胞附属物，从几乎所有哺乳动物细胞类型中伸出。它们提供重要的感觉和信号功能，初级纤毛的形成或功能的缺陷导致一类称为纤毛病的人类疾病。由于初级纤毛的普遍存在，纤毛病与广泛的临床特征相关，包括囊性肾病、视网膜变性、肥胖、骨骼缺陷、性腺功能减退、嗅觉丧失、行为障碍、社交缺陷和智力残疾。与纤毛病相关的神经系统疾病的范围表明纤毛在大脑中起重要作用。事实上，哺乳动物大脑中的大多数神经元都有一个富含特异性G蛋白偶联受体（GPCR）的初级纤毛，如多巴胺受体1（D1）。据认为，神经元纤毛感测神经调质并提供专门的信号传导。然而，初级纤毛在神经元功能中的作用在很大程度上仍然未知。我们已经发现，运输的GPCR和神经元纤毛是动态的和GPCR纤毛定位的调节被破坏的人纤毛病Bardet-Biedl综合征（BBS）的小鼠模型。例如，D1在BBS小鼠的纹状体和杏仁核神经元上的纤毛中显示异常积累。有趣的是，这些小鼠表现出减少的运动活动和成年发病肥胖;表型与缺陷的D1信号传导一致。我们假设GPCR进出纤毛的运输协调受体信号传导，纤毛定位的破坏改变了GPCR信号传导的调节。本申请的目的是确定D1纤毛积累和D1纤毛定位丢失对D1表达、运输和信号传导的影响。这项工作的结果有望从根本上推进我们对纤毛在D1信号调节中的作用的理解。这些研究将为纤毛信号传导提供关键的见解，这些信号传导是建立GPCR在整个大脑神经元纤毛中定位的重要性所必需的。