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Genetic and biased agonist-mediated reductions in β-arrestin recruitment prolong cAMP signalling at glucagon family receptors

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Title: Genetic and biased agonist-mediated reductions in β-arrestin recruitment prolong cAMP signalling at glucagon family receptors
Authors: Jones, B
McGlone, ER
Fang, Z
Pickford, P
Corrêa, IR
Oishi, A
Jockers, R
Inoue, A
Kumar, S
Görlitz, F
Dunsby, C
French, PMW
Rutter, GA
Tan, TM
Tomas, A
Bloom, SR
Item Type: Journal Article
Abstract: Receptors for the peptide hormones glucagon-like peptide-1 (GLP-1R), glucose-dependent insulinotropic polypeptide (GIPR) and glucagon (GCGR) are important regulators of insulin secretion and energy metabolism. GLP-1R agonists have been successfully deployed for the treatment of type 2 diabetes, but it has been suggested that their efficacy is limited by target receptor desensitisation and downregulation due to recruitment of β-arrestins. Indeed, recently described GLP-1R agonists with reduced β-arrestin-2 recruitment have delivered promising results in preclinical and clinical studies. We therefore aimed to determine if the same phenomenon could apply to the closely related GIPR and GCGR. In HEK293 cells depleted of both β-arrestin isoforms the duration of G protein-dependent cAMP/PKA signalling was increased in response to the endogenous ligand for each receptor. Moreover, in wild-type cells, “biased” GLP-1, GCG and GIP analogues with selective reductions in β-arrestin-2 recruitment led to reduced receptor endocytosis and increased insulin secretion over a prolonged stimulation period, although the latter effect was only seen at high agonist concentrations. Biased GCG analogues increased the duration of cAMP signalling, but this did not lead to increased glucose output from hepatocytes. Our study provides a rationale for development of GLP-1R, GIPR and GCGR agonists with reduced β-arrestin recruitment, but further work is needed to maximally exploit this strategy for therapeutic purposes.
Issue Date: 2021
Date of Acceptance: 1-Dec-2020
URI: http://hdl.handle.net/10044/1/85112
DOI: 10.1074/jbc.ra120.016334
ISSN: 0021-9258
Publisher: American Society for Biochemistry & Molecular Biology (ASBMB)
Start Page: 1
End Page: 15
Journal / Book Title: Journal of Biological Chemistry
Volume: 296
Copyright Statement: © 2020 THE AUTHORS. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Sponsor/Funder: Imperial College Healthcare NHS Trust- BRC Funding
Medical Research Council (MRC)
Imperial College Healthcare NHS Trust- BRC Funding
Imperial College Healthcare NHS Trust- BRC Funding
The Academy of Medical Sciences
Society for Endocrinology
European Foundation for the Study of Diabetes
British Society for Neuroendocrinology
Wellcome Trust
Funder's Grant Number: RDA05 79560
MR/R010676/1
RDA29
RDC04
N/A
N/A
98102
N/A
212625/Z/18/Z
Keywords: GIP
GLP-1
biased agonism
diabetes
glucagon
membrane trafficking
molecular pharmacology
receptor endocytosis
Biochemistry & Molecular Biology
03 Chemical Sciences
06 Biological Sciences
11 Medical and Health Sciences
Publication Status: Published
Online Publication Date: 2021-01-04
Appears in Collections:Department of Metabolism, Digestion and Reproduction
Physics
Photonics
Faculty of Medicine
Faculty of Natural Sciences



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