[HTML][HTML] Spatiotemporal GLP-1 and GIP receptor signaling and trafficking/recycling dynamics induced by selected receptor mono-and dual-agonists
Molecular metabolism, 2021•Elsevier
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 …
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 …
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.
Elsevier