{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSSTR4, one of the five G protein–coupled somatostatin receptors, exhibits a heterogeneous expression profile in both endocrine tumors and non‐tumoral tissues. In gastroenteropancreatic endocrine tumors, for example, SSTR4 is identified only in a small minority of cases (see."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Its expression has also been investigated in prostate tissue, where in situ analyses have sought to clarify its presence alongside other receptor subtypes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " In conditions such as Graves’ ophthalmopathy, SSTR4 mRNA is found at relatively higher levels in retroorbital lymphocytes from affected patients compared to controls"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ", and similar profiling has been noted in fibroblasts derived from retroorbital tissue."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " Additionally, studies in gallbladder and laryngeal carcinomas indicate that altered SSTR4 expression may correlate with disease characteristics such as lymphatic spread"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ", while in pituitary adenomas it is among the less abundantly expressed subtypes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMechanistic studies in cellular models have elucidated key aspects of SSTR4 function. Experiments using HEK-293 cells demonstrate that human SSTR4 undergoes constitutive dimerization—a process crucially dependent on the receptor’s intact C-terminal tail—for proper membrane expression and efficient coupling to inhibitory G proteins. This coupling underlies its ability to reduce cyclic AMP levels and modulate downstream MAPK signaling (notably pERK1/2 and pERK5), which is associated with upregulation of cyclin-dependent kinase inhibitor p27(kip1) and subsequent inhibition of cell proliferation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its roles in cell signaling and growth regulation, SSTR4 is emerging as a key mediator in both peripheral inflammatory responses and central nervous system (CNS) modulation. In the lung, SSTR4 is localized on bronchial epithelial cells, vascular endothelium, and smooth muscle cells, and its protein levels markedly increase in response to inflammatory challenges such as endotoxin exposure and chronic cigarette smoke—effects that are largely attributable to the recruitment of sst4‐positive mononuclear cells."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " In the CNS, SSTR4 is predominantly expressed in glutamatergic neurons within pain and mood regulatory circuits, and activation of the receptor reliably decreases neuronal firing by enhancing the M-current, supporting its potential as a novel target for analgesic and antidepressant therapies."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " Notably, investigations into its gene regulation reveal that the methylation status of the SSTR4 promoter remains largely unaltered in Alzheimer’s disease, suggesting that dysregulation of SSTR4 signaling in neurodegeneration is not primarily driven by promoter hypermethylation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "M Papotti, M Bongiovanni, M Volante, et al. 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