{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nThe parathyroid hormone receptor type 2 (PTH2R) is a class B1 G protein–coupled receptor that responds primarily to its endogenous ligand, tuberoinfundibular peptide of 39 residues (TIP39), and to parathyroid hormone (PTH). In the central nervous system, PTH2R is widely distributed in discrete regions—including the central amygdaloid nucleus, hypothalamic nuclei, brainstem, and preoptic areas—suggesting roles in modulating endocrine release, emotional behaviors such as fear and anxiety, and nociceptive as well as viscerosensory processing. Moreover, analyses of genetic variation in the parathyroid hormone pathway have begun to shed light on how PTH2R may contribute to skeletal and systemic functions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the molecular level, TIP39 binding to PTH2R induces a unique activation mechanism. Recent cryogenic electron microscopy studies reveal that TIP39 adopts an atypical N-terminal loop conformation that penetrates deeply into the receptor’s transmembrane domain, an interaction that is essential for receptor activation. This ligand–receptor coupling triggers distinct intracellular signaling dynamics—such as sustained cAMP accumulation and beta–arrestin recruitment leading to receptor internalization—differentiating TIP39’s effects from those elicited by PTH. In contrast to the facilitatory roles mediated by PTH1 receptors in other tissues, PTH2R activation by TIP39 may even result in inhibitory modulation of neurotransmitter release in cardiac and renal tissues."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its central roles, PTH2R signaling has important peripheral consequences. In the growth plate, overexpression studies in transgenic mice reveal that heightened PTH2R activity decreases chondrocyte proliferation and delays differentiation, thereby perturbing endochondral ossification and reducing trabecular bone volume. In the context of the skeleton, specific PTH2R polymorphisms are associated with age–related degenerative changes in the lumbar spine. In the skin, PTH2R and TIP39 are expressed in keratinocytes where their interaction modulates intracellular calcium levels and promotes aspects of terminal differentiation; similar mechanisms have been explored as potential strategies to improve calcium transport abnormalities in models of Darier disease."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "11"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Alessandro Bisello, Danielle Manen, Dominique D Pierroz, et al. 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