Agonist-induced membrane nanodomain clustering drives GLP-1 receptor responses in pancreatic beta cells
Research output: Contribution to journal › Article
Colleges, School and Institutes
- Imperial College London
- New England Biolabs, Ipswich, Massachusetts, United States of America.
- Centre of Membrane Proteins and Receptors (COMPARE), Universities of Birmingham and Nottingham, United Kingdom.
- University College London
- University of Strasbourg, France
- Tohoku University
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.
|Publication status||Published - 20 Aug 2019|