Modulation of dopaminergic neurotransmission by ADGRL3, an adhesion GPCR associated with ADHD susceptibility

ADGRL3（一种与 ADHD 易感性相关的粘附 GPCR）对多巴胺能神经传递的调节

• 批准号: 9350414
• 负责人: Jonathan A Javitch
• 金额: $ 20.25万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-09 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9350414
• 关键词: Adhesions; Adhesives; Agonist; Animals; Architecture; Attention deficit hyperactivity disorder; Back; Behavioral; Behavioral Model; Binding; Biological Assay; Cell membrane; Cognition; Complex; Corpus striatum structure; Disease; Dopamine; Drosophila genus; Family; Fibronectins; Functional disorder; Future; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; G-substrate; GTP-Binding Proteins; Genes; Genetic; Genetic Polymorphism; Goals; Hyperactive behavior; Image; In Vitro; Integral Membrane Protein; Knockout Mice; Ligand Binding; Ligands; Magnetism; Mechanical Stress; Mechanics; Mediating; Mental Health; Morphology; Motor Activity; Mus; Mutation; N-terminal; Orphan; Pathway interactions; Patients; Peptide Hydrolases; Pharmacotherapy; Phenotype; Physiological; Predisposition; Property; Protein Array; Proteins; Proteolysis; Risk; Role; Schizophrenia; Signal Pathway; Signal Transduction; Site; Synapses; Tertiary Protein Structure; Testing; Therapeutic; Transmembrane Domain; Zebrafish; addiction; alpha-latrotoxin receptor; dopaminergic neuron; drug development; extracellular; improved; in vitro activity; in vivo; innovation; interdisciplinary approach; leucine-rich repeat protein; loss of function; mechanical force; neuropsychiatric disorder; neurotransmission; novel; receptor; screening; sensor; therapy development; tool

Project Summary Adhesion GPCRs (aGPCRs) form the second largest, yet most enigmatic class of the GPCR superfamily. Recent genetic findings show that polymorphisms in the gene encoding the adhesion G protein-coupled receptor (aGPCR) latrophilin 3 (ADGRL3) are strongly associated with an increased risk of attention deficit hyperactivity disorder (ADHD). Remarkably, in fruit flies, zebrafish and mice, disruption of ADGRL3 expression enhanced locomotor activity. In adgrl3 null mice, striatal dopamine levels were shown to be increased, suggesting that the cross-species hyperactive phenotype may be mediated through enhanced dopamine signaling. Thus, ADGRL3 represents a novel target for the development of drug treatments for ADHD and other neuropsychiatric disorders that involve dopamine dysregulation, such as schizophrenia and addiction. However, ADGRL3 remains orphan with respect to the identity of its agonists and signaling properties, and its role in dopamine neurotransmission is poorly understood. Like other aGPCRs, ADGRL3 contains a 7 transmembrane domain and an extracellular N-terminal architecture comprising an array of protein domains suitable for adhesive interactions with protein ligands. In the current proposal we aim to characterize the basic signaling properties of ADGRL3 and how they can be modulated by adhesive protein ligands. For this purpose we will use a comprehensive suite of GPCR signaling assays combined with an innovative magnetic force assay to mimic the mechanical force potentially exerted in binding of trans-synaptic ligands that function to maintain and modulate synapse morphology and organization. In parallel, we will use a combination of genetic strategies together with imaging and behavioral approaches to characterize the role of ADGRL3 in dopamine neurotransmission in vivo. This multidisciplinary approach will also serve as a platform for future studies aimed at testing the functional impact of disease mutations in ADGRL3 and in screening for modulators of ADGRL3 signaling. To achieve these goals we propose the following specific aims: 1) To identify the G protein pathways controlled by ADGRL3 and to establish the role of the N terminus in signaling and in regulating dopamine neurotransmission using (a) in vitro signaling assays and strategic ADGRL3 mutations, (b) an innovative magnetic tweezer assay to evaluate the influence of mechanical force on the activity of ADGRL3 and (c) a Drosophila behavioral model to characterize the localization and function of ADGRL3 in dopaminergic neurons in vivo. 2) To identify the mechanism by which trans-synaptic ligands modulate ADGRL3 signaling and dopamine neurotransmission by determining the effect of teneurin-1 and other ligands on ADGRL3 signaling using the in vitro and in vivo approaches described above.

项目概要 粘附 GPCR (aGPCR) 是 GPCR 超家族中第二大但也是最神秘的一类。 最近的遗传学研究结果表明，编码粘附 G 蛋白偶联基因的多态性 受体 (aGPCR) latrophilin 3 (ADGRL3) 与注意力缺陷风险增加密切相关 多动症（ADHD）。值得注意的是，在果蝇、斑马鱼和小鼠中，ADGRL3 表达受到破坏 增强的运动活动。在 adgrl3 缺失小鼠中，纹状体多巴胺水平增加， 表明跨物种的过度活跃表型可能是通过增强的多巴胺介导的 发信号。因此，ADGRL3 代表了开发 ADHD 和 ADHD 药物治疗的新靶点。 其他涉及多巴胺失调的神经精神疾病，例如精神分裂症和成瘾症。 然而，ADGRL3 就其激动剂的身份和信号传导特性而言仍然是孤儿，并且其 人们对多巴胺神经传递的作用知之甚少。与其他 aGPCR 一样，ADGRL3 包含 7 跨膜结构域和包含一系列蛋白质结构域的细胞外 N 端结构 适用于与蛋白质配体的粘附相互作用。在当前的提案中，我们的目标是描述基本的特征 ADGRL3 的信号传导特性以及它们如何通过粘附蛋白配体进行调节。为此目的 我们将使用一整套 GPCR 信号分析与创新磁力相结合 模拟跨突触配体结合中潜在施加的机械力的测定，其功能是 维持和调节突触形态和组织。同时，我们将结合遗传 结合成像和行为方法的策略来表征 ADGRL3 在多巴胺中的作用 体内神经传递。这种多学科方法也将作为未来研究的平台 测试 ADGRL3 疾病突变的功能影响以及筛选 ADGRL3 调节剂 发信号。为了实现这些目标，我们提出以下具体目标：1) 鉴定 G 蛋白 ADGRL3 控制的途径并确定 N 末端在信号传导和 使用 (a) 体外信号分析和策略 ADGRL3 调节多巴胺神经传递 突变，（b）一种创新的磁镊测定法，用于评估机械力对突变的影响 ADGRL3 的活性和（c）果蝇行为模型来表征 ADGRL3 的定位和功能 体内多巴胺能神经元中的 ADGRL3。 2) 确定跨突触配体的机制 通过确定 teneurin-1 和的作用来调节 ADGRL3 信号传导和多巴胺神经传递 使用上述体外和体内方法研究 ADGRL3 信号传导的其他配体。

项目成果

Publisher Correction: G12/13 is activated by acute tethered agonist exposure in the adhesion GPCR ADGRL3.

出版商更正：G12/13 是由粘附 GPCR ADGRL3 中的急性束缚激动剂暴露激活的。

• 发表时间: 2020-12
• 影响因子: 14.8
• 作者: Mathiasen, Signe;Palmisano, Tiago;Perry, Nicole A;Stoveken, Hannah M;Vizurraga, Ale;McEwen, Dyke P;Okashah, Najeah;Langenhan, Tobias;Inoue, Asuka;Lambert, Nevin A;Tall, Gregory G;Javitch, Jonathan A
• 通讯作者: Javitch, Jonathan A