Journal
NATURE
Volume 587, Issue 7835, Pages 650-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41586-020-2888-2
Keywords
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Categories
Funding
- UK Medical Research Council (MRC) [MC_U105185859]
- Federation of European Biochemical Societies Long-Term Fellowship
- European Union [832620]
- Swiss National Science foundation (SNF) [P2ELP3_18910]
- National Institutes of Health (NIH) [R01AG053987]
- NIH Center of Biomedical Research Excellence (COBRE)
- Core National Institute on Drug Abuse (NIDA) Center of Excellence in Omics, Systems Genetics, and the Addictome
- NIH [GM117425]
- National Science Foundation (NSF) [1935926]
- MRC [MC_PC_17156]
- UK Biotechnology and Biological Sciences Research Council (BBSRC)-iCase studentship [BB/JO14540/1]
- AstraZeneca
- Lundbeck Foundation [R313-2019-526, R218-2016-1266]
- Novo Nordisk Foundation [NNF17OC0031226]
- NSF [DGE 1256260]
- BBSRC [BB/P000649/1, BB/P00069X/1]
- European Research Council (ERC) [ERC-COG-2015-682414]
- Novo Nordisk Foundation
- American Lebanese Syrian Associated Charities (ALSAC)
- BBSRC [2120024, BB/P00069X/1, BB/P000649/1] Funding Source: UKRI
- MRC [MC_U105185859] Funding Source: UKRI
- Marie Curie Actions (MSCA) [832620] Funding Source: Marie Curie Actions (MSCA)
- Direct For Biological Sciences [1935926] Funding Source: National Science Foundation
- Div Of Molecular and Cellular Bioscience [1935926] Funding Source: National Science Foundation
- Lundbeck Foundation [313-2019-526, R218-2016-1266] Funding Source: researchfish
- Novo Nordisk Fonden [NNF18OC0031226] Funding Source: researchfish
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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 sequence(1,2) or expression(3) of the receptors, leading to signalling bias when comparing diverse physiological systems(4). 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.
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