An assessment of orphan G-protein-coupled receptor-activation with L-phenylalanine

Abstract

As the largest family of cell membrane receptors in the human genome, G protein-coupled receptors (GPCRs) exist in a wide variety of body tissues with a wide range of cellular signaling functions. A large subset of these GPCRs are orphans with no determined or validated endogenous ligand, which limits studies of their function and their potential pharmacological applications. Among many possible activating ligands, amino acids are able to activate some GPCRs. We hypothesized that L-Phenylalanine (L-Phe) specifically would activate numerous GPCRs, including some orphan GPCRs. To study this, a high throughput activation screen of 277 GPCRs that included 64 orphan GPCRs was conducted with a 3 mM L-Phe treatment and compared to a vehicle treatment. This L-Phe treatment significantly activated 44 of 64 orphan GPCRs, where the GPCRs GPR88, GPR45, GPR31, CXCR7, and GPR32 exhibited the highest magnitude in activation from baseline activity levels at above seven-fold. A database search showed that the tissue distributions of these orphan GPCRs were also variable, with highest GPCR expression reported in the brain and the gastrointestinal system. These findings support the idea that L-Phe is a GPCR ligand and that it potentially deorphanizes some of these orphan GPCRs. By looking at GPCR activation with L-Phe, we can gain a greater understanding of the biological implications of L-Phe beyond protein assembly.