Combinatorial expression of functionally distinct GPCR isoforms can diversify receptor signalling response

By M. Marti-Solano, Stephanie E. Crilly, Duccio Malinverni, Christian Munk, Matthew Harris, Abigail Pearce, Tezz Quon, A. Mackenzie, Xusheng Wang, Junmin Peng and 6 more. 2020

118 citations recorded by the source corpus.

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.

Subfields: Cellular and Molecular Neuroscience, Endocrinology, Diabetes and Metabolism, Molecular Biology

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Citations in the corpus

GPCRdb in 2021: integrating GPCR sequence, structure and function (2020, background): “For receptors, GPCRdb also stores 625 distinct isoforms, which can have diverse signalling and drug responses (24), and 63 526 natural genetic variants (25).”
GPCRdb in 2023: state-specific structure models using AlphaFold2 and new ligand resources (2022, background): “Data: The updated data types span receptor sequences, isoforms (26), genetic variants (27), structures, drugs and mutations used to pinpoint ligand binding residues or (thermo)stabilize structures (28).”