Combinatorial expression of GPCR isoforms affects signalling and drug responses.
Combinatorial expression of GPCR isoforms affects signalling and drug responses.
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DOI：
10.1038/s41586-020-2888-2
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发表时间：
2020-11
期刊：
影响因子：
64.8
通讯作者：
Babu MM
中科院分区：
文献类型：
--
作者：
Marti-Solano M;Crilly SE;Malinverni D;Munk C;Harris M;Pearce A;Quon T;Mackenzie AE;Wang X;Peng J;Tobin AB;Ladds G;Milligan G;Gloriam DE;Puthenveedu MA;Babu MM
G蛋白偶联受体（gpcr）是一种跨膜蛋白，在响应细胞外信号时调节不同组织的生理。由于序列（如多态性）的变化或不同组织中受体的表达，GPCR信号传导可能有所不同。由此产生的反应差异是生理信号偏倚的重要来源。这种偏见的一个未被充分探索的来源是产生功能多样化的GPCR亚型，这些亚型在人体组织中具有不同的表达模式。在这里，我们报告了一项综合研究的结果，整合了人类组织水平转录组、GPCR序列和结构、功能注释、蛋白质组学、单细胞RNA测序、人群遗传关联研究和药理学实验的数据。我们的研究结果显示了单个GPCR基因如何分化成具有不同结构和信号特性的多个亚型，以及这些亚型的独特组合如何在不同的人体组织中表达，从而导致生理信号的差异。根据其结构变化和表达模式，一些检测到的同种异构体也可能影响药物反应，并代表了具有更好组织选择性的新药物靶点。我们的研究结果强调需要从典型的GPCR信号传导转移到上下文特定的观点，其中一个考虑如何在一个特定的系统（即一个特定的细胞类型，组织或生物体）受体同种异构体的组合表达共同影响受体信号传导。这些观察结果为理解同种异构体变异对GPCR信号反应的影响铺平了道路，并对利用这种变异作为药物开发中GPCR选择性的来源具有重要意义。
G protein-coupled receptors (GPCRs) are transmembrane proteins that modulate physiology across diverse tissues in response to extracellular signals. GPCR signalling can differ due to variation in the sequence (e.g. polymorphisms) or in the expression of receptors in different tissues. The resulting differences in response are an important source of physiological signalling bias. An underexplored source of such bias is the generation of functionally diverse GPCR isoforms that can have distinct patterns of expression in human tissues. Here, we report the findings from a comprehensive study, integrating data from human tissue-level transcriptomes, GPCR sequences and structures, functional annotations, proteomics, single-cell RNA sequencing, population-wide genetic association studies, and pharmacological experiments. Our results show how a single GPCR gene can diversify into multiple isoforms with distinct structural and signalling properties, and how unique combinations of these isoforms can be expressed in different human tissues, contributing to differences in physiological signalling. Based on their structural changes and expression patterns, some of the detected isoforms may also influence drug response and represent new drug targets with improved tissue selectivity. Our findings highlight the need to move from a canonical to a context-specific view of GPCR signalling, in which one considers how the combinatorial expression of receptor isoforms in a specific system (i.e. a particular cell type, tissue, or organism) collectively impacts receptor signalling. These observations pave the way for understanding the impact of isoform variation on GPCR signalling response and have implications for exploiting such variation as a source of GPCR selectivity in drug development.
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影响因子：
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作者：
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