Characterization of Compartmentalized GPCR Signaling in Neurons

神经元区室化 GPCR 信号传导的表征

• 批准号: 10636909
• 负责人: Nikoleta Georgieva Tsvetanova
• 金额: $ 38.91万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10636909
• 关键词: A kinase anchoring protein; Address; Adrenergic Receptor; Behavior; Biochemical; Biological Models; Biophysics; Biosensor; Brain; Cell Nucleus; Cell membrane; Cells; Cellular biology; Chemicals; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Coupling; Cyclic AMP; Data; Development; Endocytosis; Endosomes; Ferritin; Functional disorder; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; Gases; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Heterodimerization; Human; Image; Induced pluripotent stem cell derived neurons; Learning; Light; Location; Mediating; Mediator; Memory; Memory Disorders; Mental disorders; Methods; Microscopy; Modeling; Molecular; Neurologic; Neurons; Neurosciences; Outcome; Output; Pathway interactions; Pharmacology; Physiological; Physiology; Play; Positioning Attribute; Property; Receptor Activation; Receptor Inhibition; Receptor Signaling; Regulation; Role; Shapes; Signal Transduction; Site; Specific qualifier value; Synaptic plasticity; System; Testing; Translational Regulation; Translations; Work; cell type; experimental study; genome-wide; improved; insight; interdisciplinary approach; nervous system disorder; neuropsychiatric disorder; neurotransmission; novel; pharmacologic; phosphoric diester hydrolase; programs; receptor; receptor function; response; ribosome profiling; transcriptional reprogramming; transcriptome sequencing

More than a third of all G protein-coupled receptors (GPCRs) are expressed in the brain, where they modulate synaptic plasticity, memory and behavior, and also contribute to the pathophysiology of neuropsychiatric disorders. Therefore, improved understanding of how GPCRs several neurological and operate in neurons is fundamentally important to neuroscience, and will enable mechanism-based discovery of more selective and efficient therapies for memory disorders and mental illness. In this proposal, we build on our transformative finding that receptor activation on endosomal compartments underlies unique cellular responses. We propose to explore the molecular consequences of endosomal receptor signaling in neurons, and to investigate how neurons discriminate between distinct sites of local activation. We focus on the prototypical β2-adrenoceptor (β2-AR), a recognized mediator of neuronal function, to test the hypothesis that the molecular composition of signaling complexes present at endosomes is distinct from the plasma membrane resulting in unique neuronal outcomes upon β2-AR activation. We will employ an interdisciplinary approach in human iPSC-derived neurons to 1) delineate the consequences of compartmentalized β2-AR signaling on transcriptional reprogramming, 2) elucidate the role of plasma membrane- and endosomal β2-ARs in translational regulation of gene expression, and 3) determine how the endosome induces spatially biased GPCR responses. Successful completion of these studies will illuminate how spatial GPCR regulation is established, and how it shapes critical neuronal outputs of this pathway.

超过三分之一的 G 蛋白偶联受体 (GPCR) 在大脑中表达，它们在大脑中调节 突触可塑性、记忆和行为，也有助于病理生理学 神经精神疾病。因此，加深了对 GPCR 如何 一些神经系统和 在神经元中运作的是 对于神经科学来说至关重要，并将使得基于机制的发现更具选择性和 治疗记忆障碍和精神疾病的有效疗法。在这项提案中，我们以我们的变革性基础为基础 发现内体区室上的受体激活是独特的细胞反应的基础。我们建议 探索神经元内体受体信号传导的分子后果，并研究如何 神经元区分不同的局部激活位点。我们关注原型 β2-肾上腺素受体 （β2-AR），一种公认的神经元功能调节剂，以检验以下假设： 内体中存在的信号复合物与质膜不同，导致独特的神经元 β2-AR 激活后的结果。我们将采用跨学科方法研究人类 iPSC 衍生神经元 1) 描述区室化 β2-AR 信号转导对转录重编程的影响，2) 阐明质膜和内体 β2-AR 在基因表达翻译调控中的作用， 3) 确定内体如何诱导空间偏向的 GPCR 反应。顺利完成这些 研究将阐明空间 GPCR 调控是如何建立的，以及它如何塑造关键神经元输出 这条途径。