PTH2R encodes the parathyroid hormone 2 receptor, a class B G-protein-coupled receptor that specifically binds parathyroid hormone-related peptides, particularly TIP39 (tuberoinfundibular peptide of 39 residues) 1. The receptor activates adenylyl cyclase through stimulatory G proteins (Gs), with recent structural studies revealing unique small-molecule binding sites at the cytoplasmic interface 2. PTH2R demonstrates broad tissue expression, including robust distribution throughout the central nervous system and presence in developing zebrafish otic vesicles and heart 3. In skin, PTH2R localizes to the spinous-granular layers of epidermis, where TIP39/PTH2R signaling regulates intracellular calcium and keratinocyte differentiation, with PTH2R knockout mice showing increased epidermal thickness 4. Clinical significance includes associations with skeletal disorders, as PTH2R gene variants correlate with age-related lumbar spine degenerative changes 5, and gene disruption has been linked to non-syndromic craniosynostosis 6. Environmental factors like PFOA and PFOS exposure are associated with reduced PTH2R expression in women, potentially contributing to osteoarthritis pathogenesis 7. The receptor's neurological functions include modulation of auditory, nociceptive, and sexual maturation processes 1.