by Teresa Buenaventura, Stavroula Bitsi, William E. Laughlin, Thomas Burgoyne, Zekun Lyu, Affiong I. Oqua, Hannah Norman, Emma R. McGlone, Andrey S. Klymchenko, Ivan R. Corrêa Jr, Abigail Walker, Asuka Inoue, Aylin Hanyaloglu, Jak Grimes, Zsombor Koszegi, Davide Calebiro, Guy A. Rutter, Stephen R. Bloom, Ben Jones, Alejandra Tomas
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.