GLP-1R signaling neighborhoods associate with the susceptibility to adverse drug reactions of incretin mimetics
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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.
Originalsprog | Engelsk |
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Artikelnummer | 6243 |
Tidsskrift | Nature Communications |
Vol/bind | 14 |
Udgave nummer | 1 |
Antal sider | 13 |
ISSN | 2041-1723 |
DOI | |
Status | Udgivet - 2023 |
Bibliografisk note
Funding Information:
S.C.W. is supported by the Swedish Society for Medical Research (P18-0098; PD20-0153). S.K. acknowledges funding from the Onassis Foundation (F ZR 072-1/ 2021-2022). P.S. is funded by the Swedish Research Council (2022-00323). N.A.L. is supported by National Institutes of Health grants GM130142 and GM145284. A.S.H. is supported by the Lundbeck Foundation (R278-2018-180). M.B. is funded by the CIHR (FDN-148431) and holds a Canada Research Chair in Signal Transduction and Molecular Pharmacology. V.M.L. is supported by the Swedish Research Council (grant agreement numbers 2019-01837 and 2021-02801), by the EU/EFPIA/OICR/McGill/KTH/Diamond Innovative Medicines Initiative 2 Joint Undertaking (EUbOPEN grant number 875510), by the Swedish Strategic Research Programme in Diabetes (SFO Diabetes) and Stem Cells and Regenerative Medicine (SFO StratRegen), by the European Union’s Horizon 2020 research and innovation program U-PGx (grant agreement number 668353), and by the Robert Bosch Foundation, Stuttgart, Germany.
Publisher Copyright:
© 2023, Springer Nature Limited.
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