PTH1R is a G-protein-coupled receptor that binds parathyroid hormone (PTH) and parathyroid hormone-related peptide (PTHLH), triggering conformational changes that activate downstream signaling via Gs proteins and adenylate cyclase to generate the second messenger cAMP. PTHLH dissociates from PTH1R more rapidly than PTH, resulting in faster decay of the cAMP response. The receptor plays essential roles in skeletal development, bone homeostasis, and calcium regulation by modulating osteoblast activity, osteocyte gene expression (including SOST, which encodes the bone formation inhibitor sclerostin), and renal calcium and phosphate handling. Losses of PTH1R function cause rare skeletal dysplasias including Blomstrand lethal chondrodysplasia and Eiken syndrome, while heterozygous PTH1R variants account for primary failure of eruption, a condition affecting tooth development 1. In the liver, PTH1R signaling in hepatic stellate cells promotes fibrosis through cAMP-dependent activation of transcriptional regulators that enhance collagen deposition 2. Clinically, PTH1R agonists—including teriparatide (PTH analogue), abaloparatide (PTHrP-like), and the investigational agent eneboparatide—are used to treat osteoporosis and hypoparathyroidism 3. Both teriparatide and abaloparatide increase bone mineral density and reduce vertebral and non-vertebral fractures in postmenopausal women, with abaloparatide showing slightly greater efficacy for major osteoporotic fractures 3, while eneboparatide enables independence from conventional therapy in hypoparathyroidism 4. Recent structural studies reveal that small-molecule agonists can bind within an intracellular pocket of PTH1R to selectively activate G-protein signaling with reduced β-arrestin engagement 5.