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Revealing the tissue-level complexity of endogenous glucagon-like peptide-1 receptor expression and signaling

Author

Listed:
  • Julia Ast

    (University of Birmingham)

  • Daniela Nasteska

    (University of Birmingham)

  • Nicholas H. F. Fine

    (University of Birmingham)

  • Daniel J. Nieves

    (University of Birmingham)

  • Zsombor Koszegi

    (University of Birmingham)

  • Yann Lanoiselée

    (University of Birmingham)

  • Federica Cuozzo

    (University of Birmingham)

  • Katrina Viloria

    (University of Birmingham)

  • Andrea Bacon

    (University of Birmingham)

  • Nguyet T. Luu

    (University of Birmingham
    University of Birmingham)

  • Philip N. Newsome

    (University of Birmingham
    University of Birmingham)

  • Davide Calebiro

    (University of Birmingham)

  • Dylan M. Owen

    (University of Birmingham)

  • Johannes Broichhagen

    (Leibniz-Forschungsinstitut für Molekulare Pharmakologie)

  • David J. Hodson

    (University of Birmingham
    University of Oxford)

Abstract

The glucagon-like peptide-1 receptor (GLP1R) is a class B G protein-coupled receptor (GPCR) involved in glucose homeostasis and food intake. GLP1R agonists (GLP1RA) are widely used in the treatment of diabetes and obesity, yet visualizing the endogenous localization, organization and dynamics of a GPCR has so far remained out of reach. In the present study, we generate mice harboring an enzyme self-label genome-edited into the endogenous Glp1r locus. We also rationally design and test various fluorescent dyes, spanning cyan to far-red wavelengths, for labeling performance in tissue. By combining these technologies, we show that endogenous GLP1R can be specifically and sensitively detected in primary tissue using multiple colors. Longitudinal analysis of GLP1R dynamics reveals heterogeneous recruitment of neighboring cell subpopulations into signaling and trafficking, with differences observed between GLP1RA classes and dual agonists. At the nanoscopic level, GLP1Rs are found to possess higher organization, undergoing GLP1RA-dependent membrane diffusion. Together, these results show the utility of enzyme self-labels for visualization and interrogation of endogenous proteins, and provide insight into the biology of a class B GPCR in primary cells and tissue.

Suggested Citation

  • Julia Ast & Daniela Nasteska & Nicholas H. F. Fine & Daniel J. Nieves & Zsombor Koszegi & Yann Lanoiselée & Federica Cuozzo & Katrina Viloria & Andrea Bacon & Nguyet T. Luu & Philip N. Newsome & David, 2023. "Revealing the tissue-level complexity of endogenous glucagon-like peptide-1 receptor expression and signaling," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-022-35716-1
    DOI: 10.1038/s41467-022-35716-1
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    References listed on IDEAS

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    1. Romina J. Bevacqua & Xiaoqing Dai & Jonathan Y. Lam & Xueying Gu & Mollie S. H. Friedlander & Krissie Tellez & Irene Miguel-Escalada & Silvia Bonàs-Guarch & Goutham Atla & Weichen Zhao & Seung Hyun Ki, 2021. "CRISPR-based genome editing in primary human pancreatic islet cells," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    2. Titiwat Sungkaworn & Marie-Lise Jobin & Krzysztof Burnecki & Aleksander Weron & Martin J. Lohse & Davide Calebiro, 2017. "Single-molecule imaging reveals receptor–G protein interactions at cell surface hot spots," Nature, Nature, vol. 550(7677), pages 543-547, October.
    3. Rahul Dhandapani & Cynthia Mary Arokiaraj & Francisco J. Taberner & Paola Pacifico & Sruthi Raja & Linda Nocchi & Carla Portulano & Federica Franciosa & Mariano Maffei & Ahmad Fawzi Hussain & Fernanda, 2018. "Control of mechanical pain hypersensitivity in mice through ligand-targeted photoablation of TrkB-positive sensory neurons," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
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