PTH2R

PTH2R (parathyroid hormone 2 receptor) is a class B G protein-coupled receptor that selectively recognizes parathyroid hormone family ligands and functions as the principal receptor for the neuropeptide tuberoinfundibular peptide of 39 residues (TIP39)^[1][2]. Upon ligand binding, PTH2R activates G protein-dependent signaling pathways, including cAMP generation and intracellular calcium mobilization, thereby regulating neuroendocrine and cellular responses^[3][4]. Mechanistically, the TIP39-PTH2R axis participates in stress adaptation, thermoregulation, nociceptive processing, hormone release, and other central neuroendocrine functions demonstrated in genetic and pharmacological models^[5][6]. In cellular systems, PTH2R signaling inhibits proliferation and alters chondrocyte differentiation through modulation of SOX9 expression, supporting a role in skeletal developmental processes^[7]. Disease and experimental evidence further links PTH2R signaling to neurobehavioral phenotypes, endocrine regulation, and tissue-specific physiological responses, making the receptor a valuable model for studying peptide GPCR biology^[5][6]. Compared with the closely related receptor PTH1R, PTH2R displays distinct ligand selectivity: TIP39 is highly selective for PTH2R, whereas PTHrP exhibits little or weak activity at this receptor, providing a key pharmacological distinction between the two receptor subtypes^[2][8][9]. For experimental applications, TIP39 serves as the prototypical endogenous agonist, while peptide antagonists derived from N-terminally truncated TIP39 variants and other receptor-selective ligands have enabled mechanistic investigation of PTH2R signaling, receptor activation, and ligand recognition^[4][9][10].