Photo-cross-linking-assisted deorphanization deciphers GPR50-L-LEN pairing in metabolism.

Area of Science:

• Biochemistry
• Molecular Biology
• Neuroendocrinology

Background:

• G-protein-coupled receptors (GPCRs) are crucial transmembrane proteins involved in cellular signaling and are key targets in drug discovery.
• A significant number of GPCRs (~100) are classified as 'orphan receptors,' meaning their endogenous ligands and biological functions remain unknown, hindering further research.

Purpose of the Study:

• To develop a generalizable platform for GPCR deorphanization using photo-cross-linking technology.
• To identify the endogenous ligand and elucidate the physiological function of the orphan receptor GPR50.

Main Methods:

• A novel photo-cross-linking-assisted platform was established for interface-selective ligand capture from native biological samples.
• The platform's sensitivity, specificity, and broad applicability were validated using various GPCR-ligand pairs.
• GPR50 was deorphanized, identifying the neuropeptide Little-LEN (L-LEN) as its endogenous ligand.

Main Results:

• The neuropeptide L-LEN was identified as the specific endogenous ligand for GPR50.
• L-LEN binding to GPR50 modulates cellular activities via downstream Gαi signaling in tissues.
• In mice, L-LEN and GPR50 were found to regulate energy expenditure and thermogenesis through brain-adipose cross-talk.

Conclusions:

• The developed platform offers an efficient approach for GPCR deorphanization from native biological samples.
• The deorphanization of GPR50 and identification of L-LEN provide critical insights into its physiological roles in energy homeostasis and thermoregulation.
• This work opens avenues for novel drug discovery targeting the GPR50-L-LEN pathway.