L-Phenylalanine activates class A orphan G protein-coupled receptors

Abstract

G protein-coupled receptors (GPCRs) are the largest family of cell membrane proteins in the human genome. They account for the majority of pharmacological targets due to their physiological diversity and implication in diseases. Despite many efforts to identify the ligands of GPCRs, there are many with no known endogenous ligand, deemed orphans. GPCRs are known to bind a wide variety of ligands, including L-amino acids. This study aimed to investigate the amino acid activation of 72 orphan receptors using a high-throughput screening (HTS) method. The signaling of six orphan receptors was significantly modulated following treatments with a 4/8X mixture of essential/non-essential amino acids: GPR12, GPR26, GPR37L1, GPR84, GPR88, and MRGPRX2. All receptors were activated by the 4/8X mixture except GPR37L1, which, following treatments with individual amino acids, its decrease in signaling was attributed to L-Arg with a fold change of 0.70. The remaining receptors were all significantly activated by L-Phe. In the case of GPR12, GPR84, and GPR88, activation by L-Phe surpassed that of the 4/8X amino acid mixture with fold changes of 2.66, 2.56, and 5.35, respectively, suggesting possible competitive inhibition during the 4/8X treatment. These results suggest that, through activation of GPCRs, L-Phe may play a much more significant role in metabolic processes than once thought. Determination of the biological relevance of this signaling may one day present a great therapeutic potential for future drug discovery.