Combinatorial expression of GPCR isoforms affects signalling and drug responses
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Combinatorial expression of GPCR isoforms affects signalling and drug responses. / Marti-Solano, Maria; Crilly, Stephanie E.; Malinverni, Duccio; Munk, Christian; Harris, Matthew; Pearce, Abigail; Quon, Tezz; Mackenzie, Amanda E.; Wang, Xusheng; Peng, Junmin; Tobin, Andrew B.; Ladds, Graham; Milligan, Graeme; Gloriam, David E.; Puthenveedu, Manojkumar A.; Babu, M. Madan.
In: Nature, Vol. 587, 2020, p. 650-656.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Combinatorial expression of GPCR isoforms affects signalling and drug responses
AU - Marti-Solano, Maria
AU - Crilly, Stephanie E.
AU - Malinverni, Duccio
AU - Munk, Christian
AU - Harris, Matthew
AU - Pearce, Abigail
AU - Quon, Tezz
AU - Mackenzie, Amanda E.
AU - Wang, Xusheng
AU - Peng, Junmin
AU - Tobin, Andrew B.
AU - Ladds, Graham
AU - Milligan, Graeme
AU - Gloriam, David E.
AU - Puthenveedu, Manojkumar A.
AU - Babu, M. Madan
N1 - Correction to: Nature https://doi.org/10.1038/s41586-020-2888-2Published online 04 November 2020
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
KW - PROTEIN-COUPLED RECEPTOR
KW - FUNCTIONAL SELECTIVITY
KW - PHARMACOLOGY
KW - SENSITIVITY
KW - DISCOVERY
KW - NETWORKS
KW - TARGETS
KW - VARIANT
KW - MS/MS
KW - GPR35
UR - https://www.nature.com/articles/s41586-020-2999-9
U2 - 10.1038/s41586-020-2888-2
DO - 10.1038/s41586-020-2888-2
M3 - Journal article
C2 - 33149304
VL - 587
SP - 650
EP - 656
JO - Nature
JF - Nature
SN - 0028-0836
ER -
ID: 251411632