Spatiotemporal GLP-1 and GIP receptor signaling and trafficking/recycling dynamics induced by selected receptor mono- and dual-agonists

• Main Authors: Aaron Novikoff (Author), Shannon L. O'Brien (Author), Miriam Bernecker (Author), Gerald Grandl (Author), Maximilian Kleinert (Author), Patrick J. Knerr (Author), Kerstin Stemmer (Author), Martin Klingenspor (Author), Anja Zeigerer (Author), Richard DiMarchi (Author), Matthias H. Tschöp (Author), Brian Finan (Author), Davide Calebiro (Author), Timo D. Müller (Author)
• Format: Book
• Published: Elsevier, 2021-07-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

Objective: We 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. Methods: Receptor G protein recruitment and internalization/trafficking dynamics were assessed using bioluminescence resonance energy transfer (BRET)-based technology and live-cell HILO microscopy. Results: Relative 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. Conclusions: Our 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.

Item Description

2212-8778
10.1016/j.molmet.2021.101181