{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTSHR is a prototypical G protein–coupled receptor that mediates the effects of thyroid‐stimulating hormone (TSH) on thyroid physiology. Extensive structure–function studies have shown that its large, glycoprotein hormone–binding ectodomain is critical for ligand (TSH or thyrostimulin) recognition, receptor activation, and even antibody modulation. Detailed analyses including site‐directed mutagenesis, molecular modeling, and biophysical approaches have revealed that TSHR can exist as oligomeric complexes capable of negative cooperativity, and that ligand binding promotes a conformational switch—from a tethered inverse agonist state toward an active form—thereby triggering predominant cAMP signaling. These studies also indicate that alternative ligands (for example, thyrostimulin and even hCG in certain ectodomain mutants) can activate TSHR through distinct binding interfaces, offering insights into both its normal signaling and pathological autoantibody–mediated activation observed in Graves’ disease."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "16"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nGenetic and epigenetic modulation of TSHR plays a key role in thyroid disorders. A series of studies have demonstrated that single nucleotide polymorphisms, loss‐ or gain‐of–function mutations, and even differential mRNA splicing or promoter methylation of the TSHR gene can alter receptor expression and signaling. Such genetic alterations are associated with a spectrum of clinical phenotypes ranging from partial TSH resistance and congenital hypothyroidism to the hyperactivity observed in Graves’ hyperthyroidism. In parallel, genetic association and allele‐specific expression studies have implicated TSHR variants in the disruption of central tolerance and the subsequent development of thyroid autoimmunity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "17", "end_ref": "31"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its canonical role in thyroid hormone regulation, emerging evidence indicates that TSHR is expressed and functionally active in multiple extrathyroidal tissues. Notably, TSHR expression has been detected in orbital fibroblasts—where it may interact with the insulin‐like growth factor‐1 receptor to contribute to Graves’ ophthalmopathy—as well as in skin, liver, adipocytes, ovary, and endometrium, where it appears to influence cell proliferation, differentiation, and local extracellular matrix production. In these contexts, TSHR activation (or its dysregulation via aberrant ligand specificity or autoantibody binding) can affect both paracrine and autocrine signaling processes that may contribute to metabolic alterations, adipogenesis, and local inflammatory responses."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "32", "end_ref": "47"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "T Akamizu, M M Sale, S S Rich, et al. 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