G-protein-coupled receptors (GPCRs), are the largest family of membrane proteins and mediate most of the physiological responses to hormones, neurotransmitters and environmental stimulants. At the most basic level, all GPCRs are characterized by the presence of seven membrane-spanning α-helical segments separated by alternating intracellular and extracellular loop regions¹. Orphan GPCRs are a group of GPCRs that their endogenous ligands remain unidentified and therefore their natural functions in doubt².

GPR139 is an orphan GPCRs for which amino acids L-tryptophan and L-phenylalanine, the adrenocorticotropic hormone (ACTH), and α- and β-melanocyte-stimulating hormone have been proposed as endogenous agonists³. GPR139 was found to be highly conserved across species, as the amino acid sequence of the human GPR139 protein is 96%, 92% and 70% identical to the mouse, chicken and zebrafish orthologs, respectively. According to mRNA expression levels GPR139 is mainly expressed in the central nervous system (CNS). GPR139 has been reported to activate several G protein pathways of which Gq/11 is the primary one⁴.