{"id":"doi:10.1016/j.molmet.2021.101181","kind":"article","title":"Spatiotemporal GLP-1 and GIP receptor signaling and trafficking/recycling dynamics induced by selected receptor mono- and dual-agonists","authors":["Novikoff A","O'Brien SL","Bernecker M","Grandl G","Kleinert M","Knerr PJ","Stemmer K","Klingenspor M","Zeigerer A","DiMarchi R","Tschöp MH","Finan B","Calebiro D","Müller TD"],"author_count":14,"year":2021,"published":"2021-02-06","venue":"Molecular metabolism","cited_by":87,"doi":"10.1016/j.molmet.2021.101181","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1016/j.molmet.2021.101181","archive_url":"https://space-kitty.com/papers/doi:10.1016/j.molmet.2021.101181","updated":null,"pmid":"33556643","pmcid":"PMC7921015","openalex_id":null,"pdf_url":"https://europepmc.org/articles/PMC7921015/pdf","abstract":"Objective We assessed the spatiotemporal GLP-1 and GIP receptor signaling, trafficking, and recycling dynamics of GIPR mono-agonists, GLP-1R mono-agonists including semaglutide, and GLP-1/GIP dual-agonists MAR709 and tirzepatide. Methods Receptor G protein recruitment and internalization/trafficking dynamics were assessed using bioluminescence resonance energy transfer (BRET)-based technology and live-cell HILO microscopy. Results Relative to native and acylated GLP-1 agonists, MAR709 and tirzepatide showed preserved maximal cAMP production despite partial Gα s recruitment paralleled by diminished ligand-induced receptor internalization at both target receptors. Despite MAR709's lower internalization rate, GLP-1R co-localization with Rab11-associated recycling endosomes was not different between MAR709 and GLP-1R specific mono-agonists. Conclusions Our data indicated that MAR709 and tirzepatide induce unique spatiotemporal GLP-1 and GIP receptor signaling, trafficking, and recycling dynamics relative to native peptides, semaglutide, and matched mono-agonist controls. These findings support the hypothesis that the structure of GLP-1/GIP dual-agonists confer a biased agonism that, in addition to its influence on intracellular signaling, uniquely modulates receptor trafficking.","abstract_license":"CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)","license":"CC-BY","is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":[],"details":null,"provenance":"europepmc","attribution":"Abstract of \"Spatiotemporal GLP-1 and GIP receptor signaling and trafficking/recycling dynamics induced by selected receptor mono- and dual-agonists\" by Novikoff A, O'Brien SL, Bernecker M et al., https://doi.org/10.1016/j.molmet.2021.101181, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified.","topics":[{"slug":"glp1-metabolic","name":"GLP-1 & Incretin Therapies","domain_slug":"medicine"}],"cited_in_dossiers":[]}