The Orphan Receptor GPR151: Discovery, Expression, and Emerging Biological Significance

G protein-coupled receptors (GPCRs) are among the most prominent druggable targets in the human genome, accounting for approximately 40% of marketed drugs. Despite this, current GPCR-targeted therapies address only about 10% of the GPCRs encoded in the genome. Expanding our knowledge of the remaining "orphan" GPCRs represents a critical frontier in drug discovery. GPR151 emerges as a compelling target due to its distinct expression in the habenula complex, spinal cord neurons, and dorsal root ganglia. This receptor is highly conserved across mammals and possesses orthologs in species such as zebrafish and chickens, underscoring its evolutionarily conserved role in fundamental mammalian processes. Although the precise function of GPR151 remains unknown, it has been strongly implicated in pain modulation and reward-seeking behavior. These attributes position GPR151 as a promising candidate for the development of targeted and specialized pharmacological therapies. This review summarizes the current literature on GPR151, including its discovery, structure, mechanisms, anatomical distribution, and functional roles, while also exploring potential directions for future research.