Agonist-induced membrane nanodomain clustering drives GLP-1 receptor responses in pancreatic beta cells.
Fiche publication
Date publication
août 2019
Journal
PLoS biology
Auteurs
Membres identifiés du Cancéropôle Est :
Dr KLYMCHENKO Andrey
Tous les auteurs :
Buenaventura T, Bitsi S, Laughlin WE, Burgoyne T, Lyu Z, Oqua AI, Norman H, McGlone ER, Klymchenko AS, Corrêa IR, Walker A, Inoue A, Hanyaloglu A, Grimes J, Koszegi Z, Calebiro D, Rutter GA, Bloom SR, Jones B, Tomas A
Lien Pubmed
Résumé
The glucagon-like peptide-1 receptor (GLP-1R), a key pharmacological target in type 2 diabetes (T2D) and obesity, undergoes rapid endocytosis after stimulation by endogenous and therapeutic agonists. We have previously highlighted the relevance of this process in fine-tuning GLP-1R responses in pancreatic beta cells to control insulin secretion. In the present study, we demonstrate an important role for the translocation of active GLP-1Rs into liquid-ordered plasma membrane nanodomains, which act as hotspots for optimal coordination of intracellular signaling and clathrin-mediated endocytosis. This process is dynamically regulated by agonist binding through palmitoylation of the GLP-1R at its carboxyl-terminal tail. Biased GLP-1R agonists and small molecule allosteric modulation both influence GLP-1R palmitoylation, clustering, nanodomain signaling, and internalization. Downstream effects on insulin secretion from pancreatic beta cells indicate that these processes are relevant to GLP-1R physiological actions and might be therapeutically targetable.
Référence
PLoS Biol.. 2019 Aug;17(8):e3000097