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GPCR亚型的组合表达可影响信号传导和药物反应
2020-11-06 20:06

美国圣裘德儿童研究医院M. Madan Babu和英国剑桥大学MRC分子生物实验室Maria Marti-Solano小组合作取得一项新成果。经过不懈努力,他们发现组合表达G蛋白偶联受体(GPCR)的不同亚型可影响信号传导和药物反应。2020年11月4日,《自然》在线发表了这项成果。

在本研究中,研究人员整合了来自人组织水平转录组、GPCR序列和结构、蛋白质组学、单细胞转录组学、全人群遗传关联研究和药理实验的数据。研究人员揭示了单个GPCR基因如何能够多样化形成具有不同信号特性的几种异构体,以及在不同组织中表达独特的异构体组合如何能够产生不同的信号状态。根据它们的结构变化和表达模式,某些检测到的异构体可能会影响细胞对药物的反应,其可能成为研发具有更高组织选择性药物的新靶点。

该研究表明了需要从针对典型GPCR信号转变为组织特异性GPCR的观点,该观点考虑了特定细胞类型、组织或生物体中异构体的组合表达如何共同影响受体信号传导和药物反应。

据了解,GPCR是可响应细胞外信号从而调节整个机体组织生理活动的膜蛋白。因为受体序列或表达发生变化,GPCR介导的信号传导可能会有所不同,从而在比较各种生理系统时会导致信号传导偏倚。未能充分探究这种偏倚的原因是功能多样GPCR异构体的产生,这些异构体在不同组织中具有不同的表达模式。

附:英文原文

Title: Combinatorial expression of GPCR isoforms affects signalling and drug responses

Author: Maria Marti-Solano, Stephanie E. Crilly, Duccio Malinverni, Christian Munk, Matthew Harris, Abigail Pearce, Tezz Quon, Amanda E. Mackenzie, Xusheng Wang, Junmin Peng, Andrew B. Tobin, Graham Ladds, Graeme Milligan, David E. Gloriam, Manojkumar A. Puthenveedu, M. Madan Babu

Issue&Volume: 2020-11-04

Abstract: G-protein-coupled receptors (GPCRs) are membrane proteins that modulate physiology across human tissues in response to extracellular signals. GPCR-mediated signalling can differ because of changes in the sequence1,2 or expression3 of the receptors, leading to signalling bias when comparing diverse physiological systems4. An underexplored source of such bias is the generation of functionally diverse GPCR isoforms with different patterns of expression across different tissues. Here we integrate data from human tissue-level transcriptomes, GPCR sequences and structures, proteomics, single-cell transcriptomics, population-wide genetic association studies and pharmacological experiments. We show how a single GPCR gene can diversify into several isoforms with distinct signalling properties, and how unique isoform combinations expressed in different tissues can generate distinct signalling states. Depending on their structural changes and expression patterns, some of the detected isoforms may influence cellular responses to drugs and represent new targets for developing drugs with improved tissue selectivity. Our findings highlight the need to move from a canonical to a context-specific view of GPCR signalling that considers how combinatorial expression of isoforms in a particular cell type, tissue or organism collectively influences receptor signalling and drug responses. Transcriptomics, proteomics, single-cell RNA sequencing, population-wide genetic association studies and structure–function analyses provide a picture of how the differential expression of G-protein-coupled receptor isoforms can diversify signalling in different tissues.

DOI: 10.1038/s41586-020-2888-2

Source: https://www.nature.com/articles/s41586-020-2888-2

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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