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

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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
URI: http://hdl.handle.net/10044/1/73054
DOI: https://doi.org/10.6084/m9.figshare.c.4592000
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 (http://creativecommons.org/licenses/by/4.0/), 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
15/0005374
212625/Z/18/Z
MR/R010676/1
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: https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3000097
Online Publication Date: 2019-08-20
Appears in Collections:Division of Surgery
Faculty of Medicine



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