Acylation of the Incretin Peptide Exendin-4 Directly Impacts Glucagon-Like Peptide-1 Receptor Signaling and Trafficking - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Molecular Pharmacology Année : 2021

Acylation of the Incretin Peptide Exendin-4 Directly Impacts Glucagon-Like Peptide-1 Receptor Signaling and Trafficking

Résumé

The glucagon-like peptide-1 receptor (GLP-1R) is a class B G protein- coupled receptor and mainstay therapeutic target for the treatment of type 2 diabetes and obesity. Recent reports have highlighted how biased agonism at the GLP-1R affects sustained glucose-stimulated insulin secretion through avoidance of desensitization and downregulation. A number of GLP-1R agonists (GLP-1RAs) feature a fatty acid moiety to prolong their pharmacokinetics via increased albumin binding, but the potential for these chemical changes to influence GLP-1R function has rarely been investigated beyond potency assessments for cAMP. Here, we directly compare the prototypical GLP-1RA exendin-4 with its Cterminally acylated analog, exendin-4-C16. We examine relative propensities of each ligand to recruit and activate G proteins and b-arrestins, endocytic and postendocytic trafficking profiles, and interactions with model and cellular membranes in HEK293 and HEK293T cells. Both ligands had similar cAMP potency, but exendin- 4-C16 showed ∼2.5-fold bias toward G protein recruitment and a ∼60% reduction in b-arrestin-2 recruitment efficacy compared with exendin-4, as well as reduced GLP-1R endocytosis and preferential targeting toward recycling pathways. These effects were associated with reduced movement of the GLP-1R extracellular domain measured using a conformational biosensor approach and a ∼70%increase in insulin secretion in INS-1 832/3 cells. Interactions with plasma membrane lipids were enhanced by the acyl chain. Exendin-4-C16 showed extensive albumin binding and was highly effective for lowering of blood glucose in mice over at least 72 hours. Our study highlights the importance of a broad approach to the evaluation of GLP-1RA pharmacology.
Fichier principal
Vignette du fichier
319.full.pdf (3.62 Mo) Télécharger le fichier
Origine Fichiers éditeurs autorisés sur une archive ouverte

Dates et versions

hal-03535615 , version 1 (22-02-2022)

Licence

Identifiants

Citer

Maria Lucey, Tanyel Ashik, Amaara Marzook, Yifan Wang, Joëlle Goulding, et al.. Acylation of the Incretin Peptide Exendin-4 Directly Impacts Glucagon-Like Peptide-1 Receptor Signaling and Trafficking. Molecular Pharmacology, 2021, 100 (4), pp.319-334. ⟨10.1124/molpharm.121.000270⟩. ⟨hal-03535615⟩
34 Consultations
35 Téléchargements

Altmetric

Partager

Gmail Mastodon Facebook X LinkedIn More