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Novikoff, A. ; O'Brien, S.L.* ; Bernecker, M. ; Grandl, G. ; Kleinert, M. ; Knerr, P.J.* ; Stemmer, K. ; Klingenspor, M.* ; Zeigerer, A. ; DiMarchi, R.* ; Tschöp, M.H. ; Finan, B.* ; Calebiro, D.* ; Müller, T.D.

Spatiotemporal GLP-1 and GIPR receptor signaling and trafficking/recycling dynamics induced by selected receptor mono- and dual-agonists.

Mol. Metab. 49:101181 (2021)
Verlagsversion DOI
Open Access Gold
Creative Commons Lizenzvertrag
OBJECTIVE: We aimed to assess 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 the native and acylated GLP-1 agonists, MAR709 and tirzepatide show preserved maximal cAMP production despite partial Gαs 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 indicate that MAR709 and tirzepatide induce unique spatiotemporal GLP-1 and GIP receptor signaling, trafficking and recycling dynamics relative to the native peptides, semaglutide and matched mono-agonist controls. These findings support the hypothesis that the structure of the GLP-1/GIP dual-agonists confer a biased agonism that, in addition to its influence on intracellular signaling, uniquely modulates receptor trafficking.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Diabetes ; Gipr ; Glp-1r ; Obesity ; Biased Agonism ; Internalization
ISSN (print) / ISBN 2212-8778
e-ISSN 2212-8778
Zeitschrift Molecular Metabolism
Quellenangaben Band: 49, Heft: , Seiten: , Artikelnummer: 101181 Supplement: ,
Verlag Elsevier
Verlagsort Amsterdam
Begutachtungsstatus Peer reviewed