Combinatorial expression of GPCR isoforms affects signalling and drug responses

Research output: Contribution to journalJournal articleResearchpeer-review

Standard

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 journalJournal articleResearchpeer-review

Harvard

Marti-Solano, M, Crilly, SE, Malinverni, D, Munk, C, Harris, M, Pearce, A, Quon, T, Mackenzie, AE, Wang, X, Peng, J, Tobin, AB, Ladds, G, Milligan, G, Gloriam, DE, Puthenveedu, MA & Babu, MM 2020, 'Combinatorial expression of GPCR isoforms affects signalling and drug responses', Nature, vol. 587, pp. 650-656. https://doi.org/10.1038/s41586-020-2888-2

APA

Marti-Solano, M., Crilly, S. E., Malinverni, D., Munk, C., Harris, M., Pearce, A., ... Babu, M. M. (2020). Combinatorial expression of GPCR isoforms affects signalling and drug responses. Nature, 587, 650-656. https://doi.org/10.1038/s41586-020-2888-2

Vancouver

Marti-Solano M, Crilly SE, Malinverni D, Munk C, Harris M, Pearce A et al. Combinatorial expression of GPCR isoforms affects signalling and drug responses. Nature. 2020;587:650-656. https://doi.org/10.1038/s41586-020-2888-2

Author

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. / Combinatorial expression of GPCR isoforms affects signalling and drug responses. In: Nature. 2020 ; Vol. 587. pp. 650-656.

Bibtex

@article{9c0ddadc7a894fb08c86e8083a8093ae,
title = "Combinatorial expression of GPCR isoforms affects signalling and drug responses",
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 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.",
keywords = "PROTEIN-COUPLED RECEPTOR, FUNCTIONAL SELECTIVITY, PHARMACOLOGY, SENSITIVITY, DISCOVERY, NETWORKS, TARGETS, VARIANT, MS/MS, GPR35",
author = "Maria Marti-Solano and Crilly, {Stephanie E.} and Duccio Malinverni and Christian Munk and Matthew Harris and Abigail Pearce and Tezz Quon and Mackenzie, {Amanda E.} and Xusheng Wang and Junmin Peng and Tobin, {Andrew B.} and Graham Ladds and Graeme Milligan and Gloriam, {David E.} and Puthenveedu, {Manojkumar A.} and Babu, {M. Madan}",
note = "Correction to: Nature https://doi.org/10.1038/s41586-020-2888-2Published online 04 November 2020",
year = "2020",
doi = "10.1038/s41586-020-2888-2",
language = "English",
volume = "587",
pages = "650--656",
journal = "Nature",
issn = "0028-0836",
publisher = "nature publishing group",

}

RIS

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