Optical tools for visualizing and controlling human GLP-1 receptor activation with high spatiotemporal resolution
10120 Department of Chemistry
0301 basic medicine
QH301-705.5
Science
11558 Neuroscience Center Zurich
10050 Institute of Pharmacology and Toxicology
610 Medicine & health
Genetics and Molecular Biology
Glucagon-Like Peptide-1 Receptor
03 medical and health sciences
Biochemistry and Chemical Biology
Glucagon-Like Peptide 1
540 Chemistry
Humans
GLP1R
Biology (General)
neuropeptide
genetically encoded sensor
General Immunology and Microbiology
General Neuroscience
Q
R
General Medicine
photocage
Liraglutide
General Biochemistry
570 Life sciences; biology
Medicine
fluorescence
DOI:
10.7554/elife.86628
Publication Date:
2023-04-11T10:49:37Z
AUTHORS (8)
ABSTRACT
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. We demonstrate that fluorescence signal from GLPLight1 accurately reports the expected receptor conformational activation in response to pharmacological ligands with high sensitivity (max ΔF/F0=528%) and temporal resolution (τON = 4.7 s). We further demonstrated that GLPLight1 shows comparable responses to glucagon-like peptide-1 (GLP-1) derivatives as observed for the native receptor. Using GLPLight1, we established an all-optical assay to characterize a novel photocaged GLP-1 derivative (photo-GLP1) and to demonstrate optical control of GLP1R activation. Thus, the new all-optical toolkit introduced here enhances our ability to study GLP1R activation with high spatiotemporal resolution.
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