| 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 |
| Contributors: |
Imperial College Healthcare NHS Trust- BRC Funding; Medical Research Council (MRC); The Academy of Medical Sciences; Society for Endocrinology; European Foundation for the Study of Diabetes; British Society for Neuroendocrinology; Wellcome Trust |
| Source: |
15 ; 1 |
| Publisher Information: |
American Society for Biochemistry & Molecular Biology (ASBMB) |
| Publication Year: |
2020 |
| Collection: |
Imperial College London: Spiral |
| Subject Terms: |
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 |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
Journal of Biological Chemistry; http://hdl.handle.net/10044/1/85112; RDA05 79560; MR/R010676/1; RDA29; RDC04; N/A; 98102; 212625/Z/18/Z |
| DOI: |
10.1074/jbc.ra120.016334 |
| Availability: |
http://hdl.handle.net/10044/1/85112; https://doi.org/10.1074/jbc.ra120.016334 |
| Rights: |
© 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/). ; http://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.E8E9C7DF |
| Database: |
BASE |