Development of a GPR23 cell-based β-lactamase reporter assay

Area of Science:

• Neuroscience
• Pharmacology
• Molecular Biology

Background:

• G protein-coupled receptor 23 (GPR23) is implicated in crucial neurodevelopmental processes.
• Limited selective small molecule modulators for GPR23 exist, hindering research.
• Lysophosphatidic acid and its analogs are known natural ligands for GPR23.

Purpose of the Study:

• To develop a novel assay for monitoring GPR23 activity.
• To screen a large compound library for GPR23 modulators.
• To identify the first small molecule inverse agonists for GPR23.

Main Methods:

• Utilized a tetracycline-inducible system for receptor expression control.
• Employed a sensitive beta-lactamase reporter gene assay.
• Screened a library of 1.1 million compounds.

Main Results:

• Successfully developed and implemented a GPR23 activity assay.
• Identified the first small molecule inverse agonists specific for GPR23.
• The developed assay is broadly applicable to other constitutively active receptors.

Conclusions:

• The identified small molecule inverse agonists are valuable tools for GPR23 research.
• This study advances the understanding of GPR23's role in neurodevelopment.
• The assay development methodology has broad implications for GPCR research.