{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n ClC‐4, encoded by the "}, {"type": "b", "children": [{"type": "t", "text": "CLCN4"}]}, {"type": "t", "text": " gene, is a member of the CLC family that functions primarily as an electrogenic chloride/proton exchanger in intracellular membranes. Functional analyses show that ClC‐4 mediates the coupled transport of Cl⁻ and H⁺—a mechanism that contributes to endosomal acidification and thus plays an important role in regulating intracellular pH and vesicular trafficking."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In excitable tissues such as skeletal muscle, ClC‐4 exhibits pH‐sensitive chloride currents that are modulated by extracellular pH and anionic substrates"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ", while a novel N-terminal targeting motif guides its localization to endoplasmic reticulum membranes, suggesting compartment‐specific roles."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " In hepatocytes, ClC‐4 has been shown to interact with the copper transporter ATP7B to enhance copper incorporation into ceruloplasmin, thereby influencing copper metabolism."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " In the nervous system, ClC‐4 activity is critical for proper neuronal differentiation and excitability; its function supports nerve growth factor–induced neurite outgrowth via modulation of TrkA signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Disruptive mutations in "}, {"type": "b", "children": [{"type": "t", "text": "CLCN4"}]}, {"type": "t", "text": " that impair ion transport have been linked to neurodevelopmental disorders, including X‐linked intellectual disability and early-onset epilepsy."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "10"}]}, {"type": "t", "text": " Moreover, aberrant ClC‐4 expression has been implicated in the progression of colon cancer by promoting enhanced cell migration and increased resistance to proton load–induced cytotoxicity"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": ", and altered regulation of ClC‐4 by microRNAs has been associated with enamel formation defects during amelogenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": " In renal epithelial cells, hormonal factors such as prolactin can induce a ClC‐4–like anion conductance that, along with its regulation by cAMP-dependent pathways, may have implications for sodium and chloride transport."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": " Collectively, these studies underscore the multifaceted roles of ClC‐4 in intracellular pH regulation, membrane trafficking, metabolic processes, neuronal development, and disease pathogenesis"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "–."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}, {"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Alessandra Picollo, Michael Pusch "}, {"type": "b", "children": [{"type": "t", "text": "Chloride/proton antiporter activity of mammalian CLC proteins ClC-4 and ClC-5."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nature03720"}], "href": "https://doi.org/10.1038/nature03720"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16034421"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16034421"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Alexi K Alekov, Christoph Fahlke "}, {"type": "b", "children": [{"type": "t", "text": "Channel-like slippage modes in the human anion/proton exchanger ClC-4."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Gen Physiol (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1085/jgp.200810155"}], "href": "https://doi.org/10.1085/jgp.200810155"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19364886"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19364886"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "M Kawasaki, T Fukuma, K Yamauchi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification of an acid-activated Cl(-) channel from human skeletal muscles."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Physiol (1999)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1152/ajpcell.1999.277.5.C948"}], "href": "https://doi.org/10.1152/ajpcell.1999.277.5.C948"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "10564087"}], "href": "https://pubmed.ncbi.nlm.nih.gov/10564087"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Gökce Orhan, Christoph Fahlke, Alexi K Alekov "}, {"type": "b", "children": [{"type": "t", "text": "Anion- and proton-dependent gating of ClC-4 anion/proton transporter under uncoupling conditions."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biophys J (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bpj.2011.01.045"}], "href": "https://doi.org/10.1016/j.bpj.2011.01.045"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21354396"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21354396"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Hanneke Okkenhaug, Karsten-Henrich Weylandt, David Carmena, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The human ClC-4 protein, a member of the CLC chloride channel/transporter family, is localized to the endoplasmic reticulum by its N-terminus."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FASEB J (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1096/fj.05-5588fje"}], "href": "https://doi.org/10.1096/fj.05-5588fje"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17023393"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17023393"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Ting Wang, Steven A Weinman "}, {"type": "b", "children": [{"type": "t", "text": "Involvement of chloride channels in hepatic copper metabolism: ClC-4 promotes copper incorporation into ceruloplasmin."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gastroenterology (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1053/j.gastro.2004.01.015"}], "href": "https://doi.org/10.1053/j.gastro.2004.01.015"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15057754"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15057754"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "J Hur, H J Jeong, J Park, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Chloride channel 4 is required for nerve growth factor-induced TrkA signaling and neurite outgrowth in PC12 cells and cortical neurons."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neuroscience (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.neuroscience.2013.09.003"}], "href": "https://doi.org/10.1016/j.neuroscience.2013.09.003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24036377"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24036377"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Krishna R Veeramah, Laurel Johnstone, Tatiana M Karafet, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Exome sequencing reveals new causal mutations in children with epileptic encephalopathies."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Epilepsia (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/epi.12201"}], "href": "https://doi.org/10.1111/epi.12201"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23647072"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23647072"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Hailan He, Raul E Guzman, Dezhi Cao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The molecular and phenotypic spectrum of CLCN4-related epilepsy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Epilepsia (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/epi.16906"}], "href": "https://doi.org/10.1111/epi.16906"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33951195"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33951195"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "H Hu, S A Haas, J Chelly, et al. "}, {"type": "b", "children": [{"type": "t", "text": "X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Psychiatry (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/mp.2014.193"}], "href": "https://doi.org/10.1038/mp.2014.193"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25644381"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25644381"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "T Ishiguro, H Avila, S-Y Lin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Gene trapping identifies chloride channel 4 as a novel inducer of colon cancer cell migration, invasion and metastases."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Br J Cancer (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.bjc.6605536"}], "href": "https://doi.org/10.1038/sj.bjc.6605536"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20087350"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20087350"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Kaifeng Yin, Wenting Lin, Jing Guo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MiR-153 Regulates Amelogenesis by Targeting Endocytotic and Endosomal/lysosomal Pathways-Novel Insight into the Origins of Enamel Pathologies."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/srep44118"}], "href": "https://doi.org/10.1038/srep44118"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28287144"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28287144"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Megan M Greenlee, Jeremiah D Mitzelfelt, Billie Jeanne Duke, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Prolactin stimulates sodium and chloride ion channels in A6 renal epithelial cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Physiol Renal Physiol (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1152/ajprenal.00270.2014"}], "href": "https://doi.org/10.1152/ajprenal.00270.2014"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25587116"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25587116"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Songhee Jeon, Yeni Kim, In-Won Chung, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Clozapine induces chloride channel-4 expression through PKA activation and modulates CDK5 expression in SH-SY5Y and U87 cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Prog Neuropsychopharmacol Biol Psychiatry (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.pnpbp.2014.09.002"}], "href": "https://doi.org/10.1016/j.pnpbp.2014.09.002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25246152"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25246152"}]}]}]}