Combinatorial expression of GPCR isoforms affects signalling and drug responses

Marti-Solano, M. et al. (2020) Combinatorial expression of GPCR isoforms affects signalling and drug responses. Nature, 587, pp. 650-656. (doi: 10.1038/s41586-020-2888-2) (PMID:33149304)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Quon, Dr Tezz and Milligan, Professor Graeme and Tobin, Andrew and Mackenzie, Miss Amanda
Authors: Marti-Solano, M., Crilly, S. E., Malinverni, D., Munk, C., Harris, M., Pearce, A., Quon, T., Mackenzie, A. E., Wang, X., Peng, J., Tobin, A. B., Ladds, G., Milligan, G., Gloriam, D. E., Puthenveedu, M. A., and Babu, M. M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
Journal Name:Nature
Publisher:Nature Research
ISSN:0028-0836
ISSN (Online):1476-4687
Published Online:04 November 2020
Copyright Holders:Copyright © 2020 The Authors
First Published:First published in Nature 587:650-656
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
173305Defining the functional roles of the enigmatic G protein coupled receptor GPR35Graeme MilliganBiotechnology and Biological Sciences Research Council (BBSRC)BB/P000649/1MCSB - Molecular Pharmacology
173689Defining the functional role of the enigmatic G protein coupled receptor GPR35 - Leicester application - PART BAndrew TobinBiotechnology and Biological Sciences Research Council (BBSRC)BB/P00069X/1MCSB - Administration