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Abstract
ObjectiveWe assessed the spatiotemporal GLP-1 and GIP receptor signaling, trafficking, and recycling dynamics of GIPR mono-agonists, GLP-1R mono-agonists including semaglutide, and GLP-1/GIP dual-agonists MAR709 and tirzepatide. MethodsReceptor G protein recruitment and internalization/trafficking dynamics were assessed using bioluminescence resonance energy transfer (BRET)-based technology and live-cell HILO microscopy. ResultsRelative to native and acylated GLP-1 agonists, MAR709 and tirzepatide showed preserved maximal cAMP production despite partial Gαs recruitment paralleled by diminished ligand-induced receptor internalization at both target receptors. Despite MAR709's lower internalization rate, GLP-1R co-localization with Rab11-associated recycling endosomes was not different between MAR709 and GLP-1R specific mono-agonists. ConclusionsOur data indicated that MAR709 and tirzepatide induce unique spatiotemporal GLP-1 and GIP receptor signaling, trafficking, and recycling dynamics relative to native peptides, semaglutide, and matched mono-agonist controls. These findings support the hypothesis that the structure of GLP-1/GIP dual-agonists confer a biased agonism that, in addition to its influence on intracellular signaling, uniquely modulates receptor trafficking.
Highlights
Glucagon-like peptide-1 (GLP-1) is a pleiotropic hormone with broad pharmacological potential due to its ability to improve body weight, food intake, and glucose metabolism [1]
Our results show that both dual-agonists, MAR709 and tirzepatide, act as partial effectors at GLP-1R for G protein recruitment, receptor internalization, b-arrestin recruitment, Rab5þ/Rab7þ receptor trafficking, and endosomal G-protein recruitment, while retaining full-agonist capacity for cAMP production
GPCR internalization assay A GPCR internalization assay was established by measuring the loss of baseline resonance energy transfer between an intracellular plasma membrane marker Venus-KRAS and hGLP-1R-RLUC8 or hGIPR-RLUC8 [26]
Summary
Glucagon-like peptide-1 (GLP-1) is a pleiotropic hormone with broad pharmacological potential due to its ability to improve body weight, food intake, and glucose metabolism [1]. Long-acting analogs with biochemical modifications in the GLP-1 sequence have been designed to overcome these limitations and are in clinical use for treating type 2 diabetes [6,7]. Despite molecular enhancements in time action, dose-dependent adverse effects limit the maximal efficacy and overall therapeutic potential of GLP-1R mono-agonists [8]. Single chimeric molecules with dual agonism at the receptors for GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) improve body weight and glucose handling with superior potency to GLP-1R mono-agonists in preclinical [9,10] and clinical studies [11]. While GLP-1/GIP dual-agonists have advanced to phase 3 clinical trials for treating obesity and diabetes, the
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