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Characterization of Compartmentalized GPCR Signaling in Neurons

神经元区室化 GPCR 信号传导的表征

基本信息

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
项目类别：
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

项目摘要

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，并在那里进行调节