PTH2 (parathyroid hormone 2) is a neuropeptide that functions as a potent and selective agonist of the PTH2 receptor (PTH2R), primarily through G-protein coupled signaling. PTH2 activates adenylyl cyclase to increase intracellular cAMP accumulation and elevates intracellular calcium levels 1. The receptor operates via a 'two-site' binding mechanism where PTH2's C-terminal portion binds the receptor's extracellular N-terminal domain with lower binding energy contribution, while the N-terminal portion engages the juxtamembrane domain to stimulate G-protein activation 2. PTH2 is expressed throughout the central nervous system, particularly in hypothalamic nuclei, dorsal horn of the spinal cord, and the posterior intralaminar thalamus, with peripheral expression in endocrine cells 1. Recent evidence indicates PTH2 regulates social grooming behavior through PIL-MPOA neural circuits in rodents, with functional conservation in humans 3. The system also exhibits roles in nociception and potential developmental functions 4. While PTH2 expression is tightly regulated by hedgehog signaling during vertebrate development, its broader physiological roles remain incompletely characterized. The PTH2/PTH2R system represents a phylogenetically conserved neuroendocrine axis distinct from PTH1R signaling.