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

File Description SizeFormat 
journal.pbio.3000097.pdfPublished version4.62 MBAdobe PDFView/Open
Title: Agonist-induced membrane nanodomain clustering drives GLP-1 receptor responses in pancreatic beta cells.
Authors: Buenaventura, T
Bitsi, S
Laughlin, WE
Burgoyne, T
Lyu, Z
Oqua, AI
Norman, H
McGlone, ER
Klymchenko, AS
Corrêa, IR
Walker, A
Inoue, A
Hanyaloglu, A
Grimes, J
Koszegi, Z
Calebiro, D
Rutter, GA
Bloom, SR
Jones, B
Tomas, A
Item Type: Journal Article
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.
Issue Date: 20-Aug-2019
Date of Acceptance: 5-Aug-2019
ISSN: 1544-9173
Publisher: Public Library of Science (PLoS)
Start Page: 1
End Page: 40
Journal / Book Title: PLoS Biology
Volume: 17
Issue: 8
Copyright Statement: © 2019 Buenaventura et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Sponsor/Funder: Genesis Research Trust
Diabetes UK
Wellcome Trust
Medical Research Council (MRC)
Funder's Grant Number: 1064
Keywords: Developmental Biology
06 Biological Sciences
11 Medical and Health Sciences
07 Agricultural and Veterinary Sciences
Publication Status: Published
Conference Place: United States
Open Access location:
Online Publication Date: 2019-08-20
Appears in Collections:Division of Surgery
Faculty of Medicine

Items in Spiral are protected by copyright, with all rights reserved, unless otherwise indicated.

Creative Commons