The CRE Luc Mouse Model for Bioimaging Ligand Activation of G Protein-Coupled Receptors

Numerous assays have been developed to investigate the interactions between GPCRs and their ligands since GPCRs are key therapeutic targets. Reporter-based assays using the cAMP response element (CRE) coupled with bioluminescence from a luciferase reporter have been used extensively in vitro with high-throughput screens (HTS) of large chemical compound libraries. We have generated a transgenic mouse model (CRE luc) with a luciferase reporter under the control of a synthetic promoter that contains several CREs, which supports real-time bioimaging in whole animals, tissues, or primary cells of GPCR ligand activity. In the CRE luc model, GPCR signaling through the cAMP pathway can be detected from the target GPCR that is in a native cellular environment with a full complement of associated receptors and membrane constituents. Multiple independent lines have been produced with tissue expression profiles covering the major organs. The goal of the CRE luc model is to accelerate the transition from HTS to in vivo profiling of GPCR small molecule leads as well as to define the mechanism of action of GPCR drugs in three experimental formats: primary cells, tissue homogenates, and whole animal. In this chapter, we illustrate the potential of this model by presenting assays in immunology and diabetes.