GLP-1R signaling neighborhoods associate with the susceptibility to adverse drug reactions of incretin mimetics

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

GLP-1R signaling neighborhoods associate with the susceptibility to adverse drug reactions of incretin mimetics. / Wright, Shane C.; Motso, Aikaterini; Koutsilieri, Stefania; Beusch, Christian M.; Sabatier, Pierre; Berghella, Alessandro; Blondel-Tepaz, Élodie; Mangenot, Kimberley; Pittarokoilis, Ioannis; Sismanoglou, Despoina Christina; Le Gouill, Christian; Olsen, Jesper V.; Zubarev, Roman A.; Lambert, Nevin A.; Hauser, Alexander S.; Bouvier, Michel; Lauschke, Volker M.

In: Nature Communications, Vol. 14, No. 1, 6243, 2023.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Wright, SC, Motso, A, Koutsilieri, S, Beusch, CM, Sabatier, P, Berghella, A, Blondel-Tepaz, É, Mangenot, K, Pittarokoilis, I, Sismanoglou, DC, Le Gouill, C, Olsen, JV, Zubarev, RA, Lambert, NA, Hauser, AS, Bouvier, M & Lauschke, VM 2023, 'GLP-1R signaling neighborhoods associate with the susceptibility to adverse drug reactions of incretin mimetics', Nature Communications, vol. 14, no. 1, 6243. https://doi.org/10.1038/s41467-023-41893-4

APA

Wright, S. C., Motso, A., Koutsilieri, S., Beusch, C. M., Sabatier, P., Berghella, A., Blondel-Tepaz, É., Mangenot, K., Pittarokoilis, I., Sismanoglou, D. C., Le Gouill, C., Olsen, J. V., Zubarev, R. A., Lambert, N. A., Hauser, A. S., Bouvier, M., & Lauschke, V. M. (2023). GLP-1R signaling neighborhoods associate with the susceptibility to adverse drug reactions of incretin mimetics. Nature Communications, 14(1), [6243]. https://doi.org/10.1038/s41467-023-41893-4

Vancouver

Wright SC, Motso A, Koutsilieri S, Beusch CM, Sabatier P, Berghella A et al. GLP-1R signaling neighborhoods associate with the susceptibility to adverse drug reactions of incretin mimetics. Nature Communications. 2023;14(1). 6243. https://doi.org/10.1038/s41467-023-41893-4

Author

Wright, Shane C. ; Motso, Aikaterini ; Koutsilieri, Stefania ; Beusch, Christian M. ; Sabatier, Pierre ; Berghella, Alessandro ; Blondel-Tepaz, Élodie ; Mangenot, Kimberley ; Pittarokoilis, Ioannis ; Sismanoglou, Despoina Christina ; Le Gouill, Christian ; Olsen, Jesper V. ; Zubarev, Roman A. ; Lambert, Nevin A. ; Hauser, Alexander S. ; Bouvier, Michel ; Lauschke, Volker M. / GLP-1R signaling neighborhoods associate with the susceptibility to adverse drug reactions of incretin mimetics. In: Nature Communications. 2023 ; Vol. 14, No. 1.

Bibtex

@article{710eff4e14b749adb4906e9a3e690dcc,
title = "GLP-1R signaling neighborhoods associate with the susceptibility to adverse drug reactions of incretin mimetics",
abstract = "G protein-coupled receptors are important drug targets that engage and activate signaling transducers in multiple cellular compartments. Delineating therapeutic signaling from signaling associated with adverse events is an important step towards rational drug design. The glucagon-like peptide-1 receptor (GLP-1R) is a validated target for the treatment of diabetes and obesity, but drugs that target this receptor are a frequent cause of adverse events. Using recently developed biosensors, we explored the ability of GLP-1R to activate 15 pathways in 4 cellular compartments and demonstrate that modifications aimed at improving the therapeutic potential of GLP-1R agonists greatly influence compound efficacy, potency, and safety in a pathway- and compartment-selective manner. These findings, together with comparative structure analysis, time-lapse microscopy, and phosphoproteomics, reveal unique signaling signatures for GLP-1R agonists at the level of receptor conformation, functional selectivity, and location bias, thus associating signaling neighborhoods with functionally distinct cellular outcomes and clinical consequences.",
author = "Wright, {Shane C.} and Aikaterini Motso and Stefania Koutsilieri and Beusch, {Christian M.} and Pierre Sabatier and Alessandro Berghella and {\'E}lodie Blondel-Tepaz and Kimberley Mangenot and Ioannis Pittarokoilis and Sismanoglou, {Despoina Christina} and {Le Gouill}, Christian and Olsen, {Jesper V.} and Zubarev, {Roman A.} and Lambert, {Nevin A.} and Hauser, {Alexander S.} and Michel Bouvier and Lauschke, {Volker M.}",
note = "Publisher Copyright: {\textcopyright} 2023, Springer Nature Limited.",
year = "2023",
doi = "10.1038/s41467-023-41893-4",
language = "English",
volume = "14",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "nature publishing group",
number = "1",

}

RIS

TY - JOUR

T1 - GLP-1R signaling neighborhoods associate with the susceptibility to adverse drug reactions of incretin mimetics

AU - Wright, Shane C.

AU - Motso, Aikaterini

AU - Koutsilieri, Stefania

AU - Beusch, Christian M.

AU - Sabatier, Pierre

AU - Berghella, Alessandro

AU - Blondel-Tepaz, Élodie

AU - Mangenot, Kimberley

AU - Pittarokoilis, Ioannis

AU - Sismanoglou, Despoina Christina

AU - Le Gouill, Christian

AU - Olsen, Jesper V.

AU - Zubarev, Roman A.

AU - Lambert, Nevin A.

AU - Hauser, Alexander S.

AU - Bouvier, Michel

AU - Lauschke, Volker M.

N1 - Publisher Copyright: © 2023, Springer Nature Limited.

PY - 2023

Y1 - 2023

N2 - G protein-coupled receptors are important drug targets that engage and activate signaling transducers in multiple cellular compartments. Delineating therapeutic signaling from signaling associated with adverse events is an important step towards rational drug design. The glucagon-like peptide-1 receptor (GLP-1R) is a validated target for the treatment of diabetes and obesity, but drugs that target this receptor are a frequent cause of adverse events. Using recently developed biosensors, we explored the ability of GLP-1R to activate 15 pathways in 4 cellular compartments and demonstrate that modifications aimed at improving the therapeutic potential of GLP-1R agonists greatly influence compound efficacy, potency, and safety in a pathway- and compartment-selective manner. These findings, together with comparative structure analysis, time-lapse microscopy, and phosphoproteomics, reveal unique signaling signatures for GLP-1R agonists at the level of receptor conformation, functional selectivity, and location bias, thus associating signaling neighborhoods with functionally distinct cellular outcomes and clinical consequences.

AB - G protein-coupled receptors are important drug targets that engage and activate signaling transducers in multiple cellular compartments. Delineating therapeutic signaling from signaling associated with adverse events is an important step towards rational drug design. The glucagon-like peptide-1 receptor (GLP-1R) is a validated target for the treatment of diabetes and obesity, but drugs that target this receptor are a frequent cause of adverse events. Using recently developed biosensors, we explored the ability of GLP-1R to activate 15 pathways in 4 cellular compartments and demonstrate that modifications aimed at improving the therapeutic potential of GLP-1R agonists greatly influence compound efficacy, potency, and safety in a pathway- and compartment-selective manner. These findings, together with comparative structure analysis, time-lapse microscopy, and phosphoproteomics, reveal unique signaling signatures for GLP-1R agonists at the level of receptor conformation, functional selectivity, and location bias, thus associating signaling neighborhoods with functionally distinct cellular outcomes and clinical consequences.

U2 - 10.1038/s41467-023-41893-4

DO - 10.1038/s41467-023-41893-4

M3 - Journal article

C2 - 37813859

AN - SCOPUS:85173292578

VL - 14

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 6243

ER -

ID: 370472979