Optical tools for visualizing and controlling human GLP-1 receptor activation with high spatiotemporal resolution

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• The glucagon-like peptide-1 receptor (GLP1R) is vital for glucose and energy homeostasis.
• GLP1R is the target of major weight-loss drugs like semaglutide and liraglutide.
• Current tools lack the spatiotemporal resolution to study GLP1R activation dynamics precisely.

Purpose of the Study:

• To develop a novel genetically encoded sensor for high-resolution GLP1R activity monitoring.
• To establish an all-optical assay for characterizing GLP1R ligands and activation.
• To enhance the study of GLP1R conformational changes and signaling pathways.

Main Methods:

• Engineering a circularly permuted green fluorescent protein into the human GLP1R to create GLPLight1.
• Utilizing fluorescence signal changes to report receptor conformational activation.
• Developing an all-optical assay for photocaged GLP-1 derivative characterization.

Main Results:

• GLPLight1 accurately reports GLP1R conformational activation with high sensitivity (max ΔF/F0=528%) and temporal resolution (τON = 4.7 s).
• GLPLight1 demonstrated comparable responses to GLP-1 derivatives as the native receptor.
• Successful characterization of a photocaged GLP-1 derivative and demonstration of optical GLP1R control.

Conclusions:

• GLPLight1 is a sensitive and high-resolution tool for studying GLP1R activation.
• The developed all-optical toolkit advances the investigation of GLP1R signaling.
• This technology has implications for understanding metabolic diseases and optimizing GLP1R-based therapeutics.