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

Shane C. Wright (), Aikaterini Motso, Stefania Koutsilieri, Christian M. Beusch, Pierre Sabatier, Alessandro Berghella, Élodie Blondel-Tepaz, Kimberley Mangenot, Ioannis Pittarokoilis, Despoina-Christina Sismanoglou, Christian Gouill, Jesper V. Olsen, Roman A. Zubarev, Nevin A. Lambert, Alexander S. Hauser, Michel Bouvier () and Volker M. Lauschke ()
Additional contact information
Shane C. Wright: Karolinska Institutet
Aikaterini Motso: Karolinska Institutet
Stefania Koutsilieri: Karolinska Institutet
Christian M. Beusch: Karolinska Institute
Pierre Sabatier: Karolinska Institute
Alessandro Berghella: University of Copenhagen
Élodie Blondel-Tepaz: Université de Montréal
Kimberley Mangenot: Université de Montréal
Ioannis Pittarokoilis: Karolinska Institutet
Despoina-Christina Sismanoglou: Karolinska Institutet
Christian Gouill: Université de Montréal
Jesper V. Olsen: University of Copenhagen
Roman A. Zubarev: Karolinska Institute
Nevin A. Lambert: Medical College of Georgia, Augusta University
Alexander S. Hauser: University of Copenhagen
Michel Bouvier: Université de Montréal
Volker M. Lauschke: Karolinska Institutet

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-41893-4

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