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 Gα 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.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921015 | PMC |
| http://dx.doi.org/10.1016/j.molmet.2021.101181 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Lipopolysaccharide accelerates peristalsis by stimulating glucagon-like peptide-1 release from L cells in the rat proximal colon.
J Physiol
October 2024
Department of Cell Physiology, Nagoya City University Graduate School of Medical Sciences, Mizuho-ku, Nagoya, Japan.
Upon epithelial barrier dysfunction, lipopolysaccharide (LPS) stimulates glucagon-like peptide-1 (GLP-1) secretion from enteroendocrine L cells by activating Toll-like receptor 4 (TLR4). Because GLP-1 accelerates peristalsis in the proximal colon, the present study aimed to explore whether LPS facilitates colonic peristalsis by stimulating L cell-derived GLP-1 release. In isolated segments of rat proximal colon that were serosally perfused with physiological salt solution and luminally perfused with 0.
View Article and Find Full Text PDFReduced incretin receptor trafficking upon activation enhances glycemic control and reverses obesity in diet-induced obese mice.
Am J Physiol Cell Physiol
July 2024
Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Hyderabad, India.
Activation of incretin receptors by their cognate agonist augments sustained cAMP generation both from the plasma membrane as well as from the endosome. To address the functional outcome of this spatiotemporal signaling, we developed a nonacylated glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor dual agonist I-M-150847 that reduced receptor internalization following activation of the incretin receptors. The incretin receptor dual agonist I-M-150847 was developed by replacing the tryptophan cage of exendin-4 tyrosine substituted at the amino terminus with the C-terminal undecapeptide sequence of oxyntomodulin that placed lysine 30 of I-M-150847 in frame with the corresponding lysine residue of GIP.
View Article and Find Full Text PDFGeographic variation and racial disparities in adoption of newer glucose-lowering drugs with cardiovascular benefits among US Medicare beneficiaries with type 2 diabetes.
PLoS One
February 2024
Department of Pharmaceutical Outcomes & Policy, College of Pharmacy, University of Florida, Gainesville, Florida, United States of America.
Article Synopsis
- * Out of 795,469 T2D patients analyzed, only 7.2% initiated a newer GLD in the following year, with notable racial disparities, as non-Hispanic Black, American Indian/Alaska Native, Hispanic, and Asian patients were less likely to start these medications compared to non-Hispanic White patients.
- * The findings highlighted significant geographic variation in GLD initiation rates across hospital-referral regions, ranging from 2
Dual Activation of Calcium Channels Using Near-Infrared Responsive Conjugated Oligomer Nanoparticles for Precise Regulation of Blood Glucose Homeostasis.
Nano Lett
November 2023
School of Materials Science and Engineering, Hebei University of Technology, Tianjin 300130, P. R. China.
The rarity of efficient tools with spatiotemporal resolution and biocompatibility capabilities remains a major challenge for further progress and application of signaling manipulation. Herein, biomimetic conjugated oligomeric nanoparticles (CM-CONs) were developed to precisely modulate blood glucose homeostasis via the two-pronged activation of calcium channels. Under near-infrared (NIR) laser irradiation, CM-CONs efficiently generate local heat and reactive oxygen species (ROS), thereby simultaneously activating thermosensitive transient receptor potential V1 (TRPV1) and ROS-sensitive transient receptor potential A1 (TRPA1) calcium channels in small intestinal endocrine cells.
View Article and Find Full Text PDFOptical tools for visualizing and controlling human GLP-1 receptor activation with high spatiotemporal resolution.
Elife
June 2023
Institute of Pharmacology and Toxicology, University of Zürich, Zurich, Switzerland.
The glucagon-like peptide-1 receptor (GLP1R) is a broadly expressed target of peptide hormones with essential roles in energy and glucose homeostasis, as well as of the blockbuster weight-loss drugs semaglutide and liraglutide. Despite its large clinical relevance, tools to investigate the precise activation dynamics of this receptor with high spatiotemporal resolution are limited. Here, we introduce a novel genetically encoded sensor based on the engineering of a circularly permuted green fluorescent protein into the human GLP1R, named GLPLight1.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!