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Novikoff A, O'Brien SL, Bernecker M, et al. Spatiotemporal GLP-1 and GIP receptor signaling and trafficking/recycling dynamics induced by selected receptor mono- and dual-agonists. Mol Metab. 2021;49:101181doi: 10.1016/j.molmet.2021.101181.
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. (2021). Spatiotemporal GLP-1 and GIP receptor signaling and trafficking/recycling dynamics induced by selected receptor mono- and dual-agonists. Molecular metabolism, 49101181. https://doi.org/10.1016/j.molmet.2021.101181
Novikoff, Aaron, et al. "Spatiotemporal GLP-1 and GIP receptor signaling and trafficking/recycling dynamics induced by selected receptor mono- and dual-agonists." Molecular metabolism vol. 49 (2021): 101181. doi: https://doi.org/10.1016/j.molmet.2021.101181
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. Spatiotemporal GLP-1 and GIP receptor signaling and trafficking/recycling dynamics induced by selected receptor mono- and dual-agonists. Mol Metab. 2021 Jul;49:101181. doi: 10.1016/j.molmet.2021.101181. Epub 2021 Feb 06. PMID: 33556643; PMCID: PMC7921015.
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Mol Metab. 2021 Jul;49:101181. doi: 10.1016/j.molmet.2021.101181. Epub 2021 Feb 06.

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

Molecular metabolism

Aaron Novikoff, Shannon L O'Brien, Miriam Bernecker, Gerald Grandl, Maximilian Kleinert, Patrick J Knerr, Kerstin Stemmer, Martin Klingenspor, Anja Zeigerer, Richard DiMarchi, Matthias H Tschöp, Brian Finan, Davide Calebiro, Timo D Müller

Affiliations

  1. 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.
  2. 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.
  3. Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, Neuherberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany.
  4. Novo Nordisk Research Center Indianapolis, Indianapolis, IN 46241, USA.
  5. Chair for Molecular Nutritional Medicine, School of Life Sciences, Technical University of Munich, 85354 Freising, Germany.
  6. 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.
  7. Department of Chemistry, Indiana University, Bloomington, IN 47405, USA.
  8. 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.
  9. 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: [email protected].
  10. 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: [email protected].

PMID: 33556643 PMCID: PMC7921015 DOI: 10.1016/j.molmet.2021.101181

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

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.

Keywords: Biased agonism; Dual-agonists; GIPR; GLP-1R; Receptor Internalization; Receptor Trafficking

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