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

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, Davide Calebiro, Dylan M. Owen, Johannes Broichhagen () and David J. Hodson ()
Additional contact information
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
Philip N. Newsome: 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

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-022-35716-1

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