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

Research output: Contribution to journalArticle

Authors

  • 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
  • Guy A Rutter
  • Stephen R Bloom
  • Ben Jones
  • Alejandra Tomas

Colleges, School and Institutes

External organisations

  • 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

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.

Details

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