Endosomes as a multifunctional hub to control GPCR function

内体作为控制 GPCR 功能的多功能枢纽

• 批准号: 10792068
• 负责人: Braden Lobingier
• 金额: $ 13.09万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10792068
• 关键词: Address; Adrenergic Receptor; Area; Automobile Driving; Binding; Biological; Biology; Cell surface; Cells; Chemicals; Clinic; Consensus; Drug Targeting; Endosomes; Event; Family; Future; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; GTP-Binding Proteins; Genetic Engineering; Genomics; Goals; Health; Human; Kinetics; Knowledge; Mediating; Membrane; Modeling; Molecular; Pathway interactions; Pharmaceutical Preparations; Process; Proteins; Proteomics; Signal Transduction; Signaling Molecule; Signaling Protein; Sorting; Testing; Work; beta-2 Adrenergic Receptors; drug development; improved; receptor; receptor function; response; targeted treatment; trafficking

Project Summary/Abstract GPCRs are the largest family of membrane bound signaling molecules and, collectively, the target of many drugs currently used in the clinic. Classically, GPCRs were thought to be active at the cell surface and inactive while undergoing molecular sorting and trafficking events within the cell. Recent work has overturned this model. GPCRs are not quiescent inside of cells. Instead, it is now known that GPCRs can activate G protein signaling from many intracellular compartments including the endosome, and this intracellular signaling changes drug response. While efforts are already underway to harness endosomal GPCR signaling as a drug target, much is unknown about GPCR sorting at endosomes and how these trafficking processes control endosomal GPCR signaling. The goal of this proposal is to address the knowledge gap surrounding GPCR sorting at endosomes, and to determine how these pathways control endosomal signaling. In Project 1 we test the hypothesis that endosomal sorting functions as a kinetic timer to control GPCR signaling at endosomes. We examine a prototypical GPCR, the beta 2 adrenergic receptor, and the use a combination of genetic engineering and proteomics to determine how sorting controls endosomal signaling. In Project 2 we focus on two different GPCRs which signal at endosomes but lack any of the consensus endosomal sorting motifs. We use a combination of chemical biology, genomics, and proteomics to identify the proteins and pathways which mediate endosomal sorting of these receptors. Our studies seek to reveal fundamental lessons about conserved cell biological pathways while driving forward a new area for future GPCR drug development.

项目总结/摘要 GPCR是膜结合信号分子的最大家族，并且共同地是许多药物的靶点 目前在临床上使用。传统上，GPCR被认为在细胞表面是活性的，而在细胞表面是非活性的。 在细胞内经历分子分选和运输事件。最近的研究推翻了这一模式。 GPCR在细胞内不是静止的。相反，现在已知GPCR可以激活G蛋白信号传导 包括内体在内的许多细胞内区室，这种细胞内信号改变药物 反应虽然已经在努力利用内体GPCR信号传导作为药物靶标，但还有很多工作要做。 关于GPCR在内体的分选以及这些运输过程如何控制内体GPCR未知 信号该提案的目标是解决围绕核内体GPCR分选的知识缺口， 并确定这些通路如何控制内体信号传导。在项目1中，我们测试了假设， 内体分选作为动力学计时器起作用以控制内体处的GPCR信号传导。我们研究一个 原型GPCR，β 2肾上腺素能受体，以及基因工程和 蛋白质组学，以确定如何排序控制内体信号。在项目2中，我们关注两种不同的GPCR 其在内体上发出信号，但缺乏任何共有的内体分选基序。我们结合使用 化学生物学，基因组学和蛋白质组学，以确定蛋白质和途径，介导内体 对这些受体进行分类。我们的研究试图揭示关于保守细胞生物学的基本教训， 同时推动未来GPCR药物开发的新领域。

项目成果

Cannabinoid Receptor Signaling is Dependent on Sub-Cellular Location.

大麻素受体信号传导取决于亚细胞位置。

• DOI: 10.1101/2024.03.21.586146
• 发表时间: 2024
• 期刊: bioRxiv : the preprint server for biology
• 作者: Thomas,Alix;Lobingier,BradenT;Schultz,Carsten;Laguerre,Aurélien
• 通讯作者: Laguerre,Aurélien

Ligand-directed labeling of opioid receptors for covalent attachment of fluorophores or small-molecule probes.

• DOI: 10.1016/j.xpro.2023.102231
• 发表时间: 2023-04-26
• 期刊: STAR PROTOCOLS
• 作者: Adoff, Hayden;Halls, Victoria S.;Holland, Emily;Lobingier, Braden;Arttamangkul, Seksiri
• 通讯作者: Arttamangkul, Seksiri