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

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, Abigail Walker, Asuka Inoue, Aylin Hanyaloglu, Jak Grimes, Zsombor Koszegi, Davide Calebiro, Guy A Rutter, Stephen R Bloom, Ben Jones, Alejandra Tomas

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22 Citations (Scopus)
155 Downloads (Pure)

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.

Original languageEnglish
Pages (from-to)e3000097
JournalPLoS Biology
Volume17
Issue number8
DOIs
Publication statusPublished - 20 Aug 2019

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Agricultural and Biological Sciences(all)

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