{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nThe parathyroid hormone type 1 receptor (PTH1R) is a class B G protein–coupled receptor that mediates the actions of parathyroid hormone (PTH) and PTH‐related protein (PTHrP) to regulate calcium homeostasis, skeletal turnover, and bone development. Early studies revealed that activation of PTH1R by PTH stimulates multiple signaling cascades, including biphasic activation of extracellular signal–regulated kinases (ERK1/2) through rapid G protein–dependent (PKA/PKC) as well as later, β‐arrestin–dependent pathways."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": " Structural studies employing crystallography and cryo–electron microscopy have elucidated key features of the receptor’s extracellular domain—portraying a “hot dog in a bun” architecture—and the binding modes of long–acting ligands, which in turn determine receptor conformations (R⁰ versus RG) that influence the duration and intensity of signaling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to classical G protein coupling, receptor–interacting proteins have emerged as central regulators of PTH1R signaling. The receptor’s intracellular trafficking—which involves rapid internalization, recycling, and even endosomal signaling—is controlled by interactions with a host of adaptor and regulatory molecules. For instance, NHERF proteins modulate receptor desensitization and recycling, while β‐arrestins not only mediate internalization but may sustain cAMP generation by forming ternary complexes with Gβγ subunits."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": " Complex formation with transforming growth factor β (TGF‐β) type II receptor further modulates PTH1R endocytosis, and sorting nexins such as SNX27 link the receptor to the retromer complex, ensuring proper recycling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "22"}]}, {"type": "t", "text": " Moreover, mechanical stimuli and extracellular calcium can allosterically modulate ligand residence time on the receptor, further influencing the magnitude and persistence of its signaling output.\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its fundamental signaling roles, PTH1R is critically involved in skeletal physiology and pathology. Constitutive activation of the receptor in osteocytes increases bone mass and remodeling"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "23"}]}, {"type": "t", "text": ", while mutations that impair receptor function have been implicated in disorders such as enchondromatosis"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "24"}]}, {"type": "t", "text": ", primary failure of tooth eruption (PFE)"}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "25", "end_ref": "31"}]}, {"type": "t", "text": ", and compromised receptor activity is associated with altered cell differentiation in bone tumors such as osteosarcoma."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "32", "end_ref": "36"}]}, {"type": "t", "text": " Detailed mapping of ligand contact sites—for example, photolabeling experiments have highlighted critical residues (e.g., position 19) in directing interactions at the extracellular ends of transmembrane segments—further informs the molecular basis for ligand–receptor selectivity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "31"}]}, {"type": "t", "text": " In sum, insights into PTH1R signaling complexity and its modulation by ligand structure, membrane trafficking, and interacting proteins not only enhance our understanding of bone and mineral ion homeostasis but also provide promising avenues for targeted therapeutic intervention in skeletal diseases."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "23", "end_ref": "36"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Diane Gesty-Palmer, Minyong Chen, Eric Reiter, et al. 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