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Cited by 38Receptor Mechanisms and SignalingDiabetes Treatment and ManagementPancreatic function and diabetes

The Influence of Peptide Context on Signaling and Trafficking of Glucagon-like Peptide-1 Receptor Biased Agonists

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Fang, Zijian, Chen, Shiqian, Pickford, Philip, Broichhagen, Johannes, Hodson, David J., Corrêa, Ivan R., Kumar, Sunil, Görlitz, Frederik +7 more·2020·ACS Pharmacology & Translational Science
DOI 10.1021/acsptsci.0c00022PMC PMC7155199

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Abstract

Signal bias and membrane trafficking have recently emerged as important considerations in the therapeutic targeting of the glucagon-like peptide-1 receptor (GLP-1R) in type 2 diabetes and obesity. In the present study, we have evaluated a peptide series with varying sequence homology between native GLP-1 and exendin-4, the archetypal ligands on which approved GLP-1R agonists are based. We find notable differences in agonist-mediated cyclic AMP signaling, recruitment of β-arrestins, endocytosis, and recycling, dependent both on the introduction of a His → Phe switch at position 1 and the specific midpeptide helical regions and C-termini of the two agonists. These observations were linked to insulin secretion in a beta cell model and provide insights into how ligand factors influence GLP-1R function at the cellular level.

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4 of 4 references verified0 citation errors · 0 not checkable

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  • Biased GLP-1 receptor agonists derived from exendin-4 result in prolonged insulin secretion by reducing GLP-1 receptor desensitization and endocytosis, as well as mitigating GLP-1 receptor downregulation.

    “Biased GLP-1 receptor agonists derived from exendin-4 result in prolonged insulin secretion by reducing GLP-1 receptor desensitization and endocytosis, as well as mitigating GLP-1 receptor downregulation [29].”

    From New Developments in Pharmacological Treatment of Obesity and Type 2 Diabetes—Beyond and within GLP-1 Receptor Agonists (2024) · cites this paper as [29]

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Authors
Fang, Z., Chen, S., Pickford, P., Broichhagen, J., Hodson, D. J., Corrêa, I. R., Kumar, S., Görlitz, F., Dunsby, C., French, P. M. W., Rutter, G. A., Tan, T., Bloom, S. R., Tomas, A., & Jones, B.
Affiliations
  • Imperial College London (GB)
  • Leibniz-Forschungsinstitut für Molekulare Pharmakologie (DE)
  • University of Birmingham (GB)
  • New England Biolabs, Ipswich, Massachusetts 01938, United States
  • Department of Physics, Imperial College London, London, SW7 2BX, United Kingdom
  • Section of Cell Biology and Functional Genomics, Imperial College London, London, SW7 2AZ, United Kingdom
Corresponding author
Jones, Ben
ORCID
Venue
ACS Pharmacology & Translational Science
Publisher
American Chemical Society (ACS)
Published
2020-03-17
Volume
3
Issue
2
Pages
345-360
ISSN
2575-9108 (ISSN-L)
DOI
10.1021/acsptsci.0c00022
PMC
PMC7155199
OpenAlex
W3012148265
Cited by
38
References
4
Citations by year
2026: 4 · 2025: 2 · 2024: 3 · 2023: 3 · 2022: 7 · 2021: 11 · 2020: 7 · 2019: 1
FWCI
2.27
Type
journal article
Language
en
Open access
Licence
Locations
  • ACS Pharmacology & Translational Science (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • University of Birmingham Research Portal (University of Birmingham) (submittedVersion, other-oa)
  • Spiral (Imperial College London) (submittedVersion)
Funders
  • Engineering and Physical Sciences Research Council
  • FP7 Health (FP7- HEALTH- 2009- 241592)
  • Medical Research Council (MR/J0003042/1, MR/L020149/1, MR/N00275X/1, MR/R022259/1, MR/S025618/1)
  • Diabetes UK (16/0005485, 17/0005681, BDA/11/0004210, BDA/15/0005275)
  • Academy of Medical Sciences
  • National Institute for Health Research
  • Society for Endocrinology
  • European Association for the Study of Diabetes
  • Wellcome Trust (212625/Z/18/Z)
  • H2020 European Research Council (115881, 715884)
  • Biotechnology and Biological Sciences Research Council
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
Keywords
GLP-1 receptor, biased agonists, exendin-4, glucagon-like peptide-1, signal bias, cAMP signaling, β-arrestin recruitment, receptor internalization, receptor recycling, insulin secretion, pancreatic beta cells, type 2 diabetes, obesity

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