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LUXendins reveal endogenous glucagon-like peptide-1 receptor distribution and dynamics

View ORCID ProfileJulia Ast, Anastasia Arvaniti, View ORCID ProfileNicholas H.F. Fine, View ORCID ProfileDaniela Nasteska, Fiona B. Ashford, Zania Stamataki, Zsombor Koszegi, Andrea Bacon, View ORCID ProfileStefan Trapp, Ben J. Jones, View ORCID ProfileBenoit Hastoy, View ORCID ProfileAlejandra Tomas, Christopher A. Reissaus, View ORCID ProfileAmelia K. Linnemann, Elisa D’Este, View ORCID ProfileDavide Calebiro, View ORCID ProfileKai Johnsson, View ORCID ProfileTom Podewin, View ORCID ProfileJohannes Broichhagen, View ORCID ProfileDavid J. Hodson
doi: https://doi.org/10.1101/557132
Julia Ast
1Institute of Metabolism and Systems Research (IMSR), and Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham, Birmingham, UK
2Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
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Anastasia Arvaniti
1Institute of Metabolism and Systems Research (IMSR), and Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham, Birmingham, UK
2Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
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Nicholas H.F. Fine
1Institute of Metabolism and Systems Research (IMSR), and Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham, Birmingham, UK
2Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
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Daniela Nasteska
1Institute of Metabolism and Systems Research (IMSR), and Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham, Birmingham, UK
2Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
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Fiona B. Ashford
1Institute of Metabolism and Systems Research (IMSR), and Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham, Birmingham, UK
2Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
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Zania Stamataki
3Centre for Liver Research, College of Medical and Dental Sciences, Institute for Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
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Zsombor Koszegi
1Institute of Metabolism and Systems Research (IMSR), and Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham, Birmingham, UK
2Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
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Andrea Bacon
4Genome Editing Facility, Technology Hub, University of Birmingham, Birmingham, UK
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Stefan Trapp
5Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology & Pharmacology, University College London, London, UK
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Ben J. Jones
6Imperial College London, Section of Investigative Medicine, Division of Diabetes, Endocrinology and Metabolism, London, UK
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Benoit Hastoy
7Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, UK
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Alejandra Tomas
8Imperial College London, Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, London, UK
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Christopher A. Reissaus
9Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
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Amelia K. Linnemann
9Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
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Elisa D’Este
10Optical Microscopy Facility, Max Planck Institute for Medical Research, Heidelberg, Germany
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Davide Calebiro
1Institute of Metabolism and Systems Research (IMSR), and Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham, Birmingham, UK
2Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
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Kai Johnsson
11Department of Chemical Biology, Max Planck Institute for Medical Research, Heidelberg, Germany
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Tom Podewin
11Department of Chemical Biology, Max Planck Institute for Medical Research, Heidelberg, Germany
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  • For correspondence: d.hodson@bham.ac.uk johannes.broichhagen@mpimf-heidelberg.mpg.de tom.podewin@mpimf-heidelberg.mpg.de
Johannes Broichhagen
11Department of Chemical Biology, Max Planck Institute for Medical Research, Heidelberg, Germany
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  • For correspondence: d.hodson@bham.ac.uk johannes.broichhagen@mpimf-heidelberg.mpg.de tom.podewin@mpimf-heidelberg.mpg.de
David J. Hodson
1Institute of Metabolism and Systems Research (IMSR), and Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham, Birmingham, UK
2Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
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  • For correspondence: d.hodson@bham.ac.uk johannes.broichhagen@mpimf-heidelberg.mpg.de tom.podewin@mpimf-heidelberg.mpg.de
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ABSTRACT

The glucagon-like peptide-1 receptor (GLP1R) is a class B G protein-coupled receptor (GPCR) involved in metabolism. Presently, its visualization is limited to genetic manipulation, antibody detection or the use of probes that stimulate receptor activation. Herein, we present LUXendin645, a far-red fluorescent GLP1R antagonistic peptide label. LUXendin645 produces intense and specific membrane labeling throughout live and fixed tissue. GLP1R signaling can additionally be evoked when the receptor is allosterically modulated in the presence of LUXendin645. Using LUXendin645 and STED-compatible LUXendin651, we describe islet GLP1R expression patterns, reveal higher-order GLP1R organization including the existence of membrane nanodomains, and track single receptor subpopulations. We furthermore show that different fluorophores can confer agonistic behavior on the LUXendin backbone, with implications for the design of stabilized incretin-mimetics. Thus, our labeling probes possess divergent activation modes, allow visualization of endogenous GLP1R, and provide new insight into class B GPCR distribution and dynamics.

Footnotes

  • The results section has been updated to clarify GLP1R expression in non-beta cells. Specifically, subtraction of known expression in delta cells, which constitute ~20% insulin-negative cells.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted May 08, 2019.
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LUXendins reveal endogenous glucagon-like peptide-1 receptor distribution and dynamics
Julia Ast, Anastasia Arvaniti, Nicholas H.F. Fine, Daniela Nasteska, Fiona B. Ashford, Zania Stamataki, Zsombor Koszegi, Andrea Bacon, Stefan Trapp, Ben J. Jones, Benoit Hastoy, Alejandra Tomas, Christopher A. Reissaus, Amelia K. Linnemann, Elisa D’Este, Davide Calebiro, Kai Johnsson, Tom Podewin, Johannes Broichhagen, David J. Hodson
bioRxiv 557132; doi: https://doi.org/10.1101/557132
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LUXendins reveal endogenous glucagon-like peptide-1 receptor distribution and dynamics
Julia Ast, Anastasia Arvaniti, Nicholas H.F. Fine, Daniela Nasteska, Fiona B. Ashford, Zania Stamataki, Zsombor Koszegi, Andrea Bacon, Stefan Trapp, Ben J. Jones, Benoit Hastoy, Alejandra Tomas, Christopher A. Reissaus, Amelia K. Linnemann, Elisa D’Este, Davide Calebiro, Kai Johnsson, Tom Podewin, Johannes Broichhagen, David J. Hodson
bioRxiv 557132; doi: https://doi.org/10.1101/557132

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