biostudies-literatureUnknownPearce ANICHD NIH HHSBiotechnology and Biological Sciences Research CouncilThe targeting of the Glucagon-like peptide-1 receptor (GLP-1R) for diabetes and obesity is not a novel strategy, with recent therapeutics showing efficacy in weight loss and glycaemic control. However, they are also associated with side effects, including gastrointestinal disruptions and pancreatitis. Developing agonists with different signalling profiles, or that exert some tissue selectivity can circumvent these on-target, unwanted effects. Receptor activity-modifying proteins (RAMPs) offer the potential to do both, through modulation of agonist binding and signalling, as well as surface expression. The GLP-1R was found to interact with RAMP3, with the heterodimer able to bind agonist at the cell surface. RAMP3 expression biased the receptor towards Ca²⁺ mobilisation, away frobioRxiv : the preprint server for biology2025.01.24.634724https://www.ebi.ac.uk/biostudies/studies/S-EPMC12363685biostudies-literatureReceptor Activity-Modifying Protein 3 enhances GLP-1-mediated Insulin Secretion.PMC12363685R01 HD060860BB/W014831/1Harris MWinfield SLadds GPearce AKumari PSisk CMYeung HYCaron KMfalseReceptor Activity-Modifying Protein 3 enhances GLP-1-mediated Insulin Secretion.The targeting of the Glucagon-like peptide-1 receptor (GLP-1R) for diabetes and obesity is not a novel strategy, with recent therapeutics showing efficacy in weight loss and glycaemic control. However, they are also associated with side effects, including gastrointestinal disruptions and pancreatitis. Developing agonists with different signalling profiles, or that exert some tissue selectivity can circumvent these on-target, unwanted effects. Receptor activity-modifying proteins (RAMPs) offer the potential to do both, through modulation of agonist binding and signalling, as well as surface expression. The GLP-1R was found to interact with RAMP3, with the heterodimer able to bind agonist at the cell surface. RAMP3 expression biased the receptor towards Ca²⁺ mobilisation, away fro2025-01-01T00:00:00Z2025 Aug2026-05-18T03:18:08.548Z2026-05-18T03:12:44.553ZS-EPMC123636854083235510.1101/2025.01.24.634724