{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nProton-activated chloride channel 1 (PACC1), encoded by TMEM206, functions as an essential acid sensor that mediates proton-activated Cl– currents. It is broadly expressed across mammalian cells and is critical for initiating chloride flux in response to extracellular acidification. In neurons, for example, loss of PACC1 current not only abolishes acid‐induced ionic responses but also ameliorates tissue damage following ischemia, highlighting its role in acid-induced cell death and injury."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nStructurally, PACC1 assembles as a homotrimer forming a channel whose activation involves intricate pH-dependent conformational changes at the extracellular-transmembrane interface. Key residues, such as histidine 98 and lysine 319, orchestrate the proton-dependent gating and anion selectivity, thereby providing a mechanistic basis for its rapid response to pH shifts. Beyond its physiologic roles, overexpression and aberrant signaling of PACC1 have been implicated in oncogenesis. In osteosarcoma, high levels of PACC1 promote tumor proliferation, invasion, and metastasis via β-catenin-mediated upregulation of the Wnt/β-catenin pathway, establishing it as a putative oncogenic biomarker and therapeutic target."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition, in certain central nervous system tumors such as medulloblastoma, PACC1 operates in concert with other acid-sensitive proteins, including ASIC1a and the proton-activated G protein-coupled receptor OGR1, to modulate intracellular Ca2+ signals, cell volume changes, and ultimately, cell death under strongly acidic conditions. This complex interplay underscores the multifaceted role of PACC1 in both normal acid-response physiology and the pathological adaptation of cancer cells within an acidic microenvironment."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Junhua Yang, Jianan Chen, Maria Del Carmen Vitery, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PAC, an evolutionarily conserved membrane protein, is a proton-activated chloride channel."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Science (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/science.aav9739"}], "href": "https://doi.org/10.1126/science.aav9739"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31023925"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31023925"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Zheng Ruan, James Osei-Owusu, Juan Du, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Downregulation of the Proton-Activated Cl- Channel TMEM206 Inhibits Malignant Properties of Human Osteosarcoma Cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oxid Med Cell Longev (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1155/2021/3672112"}], "href": "https://doi.org/10.1155/2021/3672112"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34777684"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34777684"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Yulia Kostritskaia, Malte Klüssendorf, Yingzhou Edward Pan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Physiological Functions of the Volume-Regulated Anion Channel VRAC/LRRC8 and the Proton-Activated Chloride Channel ASOR/TMEM206."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Handb Exp Pharmacol (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/164_2023_673"}], "href": "https://doi.org/10.1007/164_2023_673"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37468723"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37468723"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Karolos-Philippos Pissas, Stefan Gründer, Yuemin Tian "}, {"type": "b", "children": [{"type": "t", "text": "Functional expression of the proton sensors ASIC1a, TMEM206, and OGR1 together with BK"}, {"type": "a", "children": [{"type": "t", "text": "sub"}], "href": "sub"}, {"type": "t", "text": "Ca"}, {"type": "a", "children": [{"type": "t", "text": "/sub"}], "href": "/sub"}, {"type": "t", "text": " channels is associated with cell volume changes and cell death under strongly acidic conditions in DAOY medulloblastoma cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Pflugers Arch (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00424-024-02964-7"}], "href": "https://doi.org/10.1007/s00424-024-02964-7"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38627262"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38627262"}]}]}]}