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PLoS Biol. 2019 Aug 20;17(8):e3000097. doi: 10.1371/journal.pbio.3000097. eCollection 2019 Aug.

Agonist-induced membrane nanodomain clustering drives GLP-1 receptor responses in pancreatic beta cells.

Author information

1
Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, London, United Kingdom.
2
Department of Cell Biology, Institute of Ophthalmology, University College London, London, United Kingdom.
3
Section of Investigative Medicine, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, London, United Kingdom.
4
Laboratoire de Bioimagerie et Pathologies, UMR CNRS 7021, University of Strasbourg, Illkirch-Strasbourg, France.
5
New England Biolabs, Ipswich, Massachusetts, United States of America.
6
Department of Surgery and Cancer, Imperial College London, London, United Kingdom.
7
Tohoku University, Sendai, Japan.
8
Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, United Kingdom.
9
Centre of Membrane Proteins and Receptors (COMPARE), Universities of Birmingham and Nottingham, Birmingham and Nottingham, United Kingdom.

Abstract

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.

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