In this section
@article{Oqua:2025:10.7554/elife.101011,
author = {Oqua, AI and Chao, K and El, Eid L and Casteller, L and Baxter, BP and Miguéns-Gómez, A and Barg, S and Jones, B and Bernardino, de la Serna J and Rouse, SL and Tomas, A},
doi = {10.7554/elife.101011},
journal = {eLife},
title = {Molecular mapping and functional validation of GLP-1R cholesterol binding sites in pancreatic beta cells},
url = {http://dx.doi.org/10.7554/elife.101011},
volume = {13},
year = {2025}
}
TY - JOUR
AB - G protein-coupled receptors (GPCRs) are integral membrane proteins which closely interact with their plasma membrane lipid microenvironment. Cholesterol is a lipid enriched at the plasma membrane with pivotal roles in the control of membrane fluidity and maintenance of membrane microarchitecture, directly impacting on GPCR stability, dynamics, and function. Cholesterol extraction from pancreatic beta cells has previously been shown to disrupt the internalisation, clustering, and cAMP responses of the glucagon-like peptide-1 receptor (GLP-1R), a class B1 GPCR with key roles in the control of blood glucose levels via the potentiation of insulin secretion in beta cells and weight reduction via the modulation of brain appetite control centres. Here, we unveil the detrimental effect of a high cholesterol diet on GLP-1R-dependent glucoregulation in vivo, and the improvement in GLP-1R function that a reduction in cholesterol synthesis using simvastatin exerts in pancreatic islets. We next identify and map sites of cholesterol high occupancy and residence time on active <jats:italic>vs</jats:italic> inactive GLP-1Rs using coarse-grained molecular dynamics (cgMD) simulations, followed by a screen of key residues selected from these sites and detailed analyses of the effects of mutating one of these, Val229, to alanine on GLP-1R-cholesterol interactions, plasma membrane behaviours, clustering, trafficking and signalling in INS-1 832/3 rat pancreatic beta cells and primary mouse islets, unveiling an improved insulin secretion profile for the V229A mutant receptor. This study (1) highlights the role of cholesterol in regulating GLP-1R responses in vivo; (2) provides a detailed map of GLP-1R - cholesterol binding sites in model membranes; (3) validates their functional relevance in beta cells; and (4) highlights their potential as locations for the rational design of novel allosteric modulators with the capacity to fine-tune GLP-1R responses.
AU - Oqua,AI
AU - Chao,K
AU - El,Eid L
AU - Casteller,L
AU - Baxter,BP
AU - Miguéns-Gómez,A
AU - Barg,S
AU - Jones,B
AU - Bernardino,de la Serna J
AU - Rouse,SL
AU - Tomas,A
DO - 10.7554/elife.101011
PY - 2025///
SN - 2050-084X
TI - Molecular mapping and functional validation of GLP-1R cholesterol binding sites in pancreatic beta cells
T2 - eLife
UR - http://dx.doi.org/10.7554/elife.101011
UR - https://doi.org/10.7554/elife.101011
VL - 13
ER -
Interested in studying a PhD at the Department of Life Sciences? Find out more about postgraduate research opportunties.