Combinatorial expression of GPCR isoforms affects signalling and drug responses

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 and M. Madan Babu ()
Additional contact information
Maria Marti-Solano: MRC Laboratory of Molecular Biology
Stephanie E. Crilly: University of Michigan
Duccio Malinverni: MRC Laboratory of Molecular Biology
Christian Munk: University of Copenhagen
Matthew Harris: University of Cambridge
Abigail Pearce: University of Cambridge
Tezz Quon: University of Glasgow
Amanda E. Mackenzie: University of Glasgow
Xusheng Wang: Center for Proteomics and Metabolomics, St Jude Children’s Research Hospital
Junmin Peng: Center for Proteomics and Metabolomics, St Jude Children’s Research Hospital
Andrew B. Tobin: University of Glasgow
Graham Ladds: University of Cambridge
Graeme Milligan: University of Glasgow
David E. Gloriam: University of Copenhagen
Manojkumar A. Puthenveedu: University of Michigan
M. Madan Babu: MRC Laboratory of Molecular Biology

Nature, 2020, vol. 587, issue 7835, 650-656

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41586-020-2888-2

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