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

Autor: Novikoff A; Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, Neuherberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany; Division of Metabolic Diseases, Department of Medicine, Technische Universität München, D-80333 Munich, Germany., O'Brien SL; Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, B15 2TT, UK; Center of Membrane Proteins and Receptors (COMPARE), Universities of Nottingham and Birmingham, Birmingham, B15 2TT, UK., Bernecker M; Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, Neuherberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany., Grandl G; Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, Neuherberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany., Kleinert M; Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, Neuherberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany., Knerr PJ; Novo Nordisk Research Center Indianapolis, Indianapolis, IN 46241, USA., Stemmer K; Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, Neuherberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany., Klingenspor M; Chair for Molecular Nutritional Medicine, School of Life Sciences, Technical University of Munich, 85354 Freising, Germany., Zeigerer A; German Center for Diabetes Research (DZD), Neuherberg, Germany; Institute for Diabetes and Cancer, Helmholtz Center Munich, 85764 Neuherberg, Germany; Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine 1, Heidelberg University Hospital, Heidelberg, Germany., DiMarchi R; Department of Chemistry, Indiana University, Bloomington, IN 47405, USA., Tschöp MH; German Center for Diabetes Research (DZD), Neuherberg, Germany; Division of Metabolic Diseases, Department of Medicine, Technische Universität München, D-80333 Munich, Germany; Helmholtz Zentrum München, Neuherberg, Germany; Technische Universität München, München, Germany., Finan B; Novo Nordisk Research Center Indianapolis, Indianapolis, IN 46241, USA., Calebiro D; Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, B15 2TT, UK; Center of Membrane Proteins and Receptors (COMPARE), Universities of Nottingham and Birmingham, Birmingham, B15 2TT, UK. Electronic address: D.Calebiro@bham.ac.uk., Müller TD; Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, Neuherberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany; Department of Pharmacology and Experimental Therapy, Institute of Experimental and Clinical Pharmacology and Toxicology, Eberhard Karls University Hospitals and Clinics, 72076 Tübingen, Germany. Electronic address: timo.mueller@helmholtz-muenchen.de.
Jazyk: angličtina
Zdroj: Molecular metabolism [Mol Metab] 2021 Jul; Vol. 49, pp. 101181. Date of Electronic Publication: 2021 Feb 06.
DOI: 10.1016/j.molmet.2021.101181
Abstrakt: 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.
(Copyright © 2021 The Authors. Published by Elsevier GmbH.. All rights reserved.)
Databáze: MEDLINE
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