The Chloride Channel ClC-4 Contributes to Endosomal Acidification and Trafficking
Mutations in the gene coding for the chloride channel ClC-5 cause Dent's disease, a disease associated with proteinuria and renal stones. Studies in ClC-5 knockout mice suggest that this phenotype is related to defective endocytosis of low molecular weight proteins and membrane proteins by the...
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| Veröffentlicht in: | The Journal of biological chemistry 2003-08, Vol.278 (31), p.29267-29277 |
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| container_title | The Journal of biological chemistry |
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| creator | Mohammad-Panah, Raha Harrison, Rene Dhani, Sonja Ackerley, Cameron Huan, Ling-Jun Wang, Yanchun Bear, Christine E. |
| description | Mutations in the gene coding for the chloride channel ClC-5 cause Dent's disease, a disease associated with proteinuria and renal stones. Studies in ClC-5 knockout mice suggest that this phenotype is related to defective endocytosis of low molecular weight proteins and membrane proteins by the renal proximal tubule. In this study, confocal micrographs of proximal tubules and cultured epithelial cells revealed that the related protein ClC-4 is expressed in endosomal membranes suggesting that this channel may also contribute to the function of this organelle. In support of this hypothesis, specific disruption of endogenous ClC-4 expression by transfection of ClC-4 antisense cDNA acidified endosomal pH and altered transferrin trafficking in cultured epithelial cells to the same extent as the specific disruption of ClC-5. Both channels can be co-immunoprecipitated, arguing that they may partially contribute to endosomal function as a channel complex. These studies prompt future investigation of the role of ClC-4 in renal function in health and in Dent's disease. Future studies will assess whether the severity of Dent's disease relates not only to the impact of particular mutations on ClC-5 but also on the consequences of those mutations on the functional expression of ClC-4. |
| doi_str_mv | 10.1074/jbc.M304357200 |
| format | Article |
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Studies in ClC-5 knockout mice suggest that this phenotype is related to defective endocytosis of low molecular weight proteins and membrane proteins by the renal proximal tubule. In this study, confocal micrographs of proximal tubules and cultured epithelial cells revealed that the related protein ClC-4 is expressed in endosomal membranes suggesting that this channel may also contribute to the function of this organelle. In support of this hypothesis, specific disruption of endogenous ClC-4 expression by transfection of ClC-4 antisense cDNA acidified endosomal pH and altered transferrin trafficking in cultured epithelial cells to the same extent as the specific disruption of ClC-5. Both channels can be co-immunoprecipitated, arguing that they may partially contribute to endosomal function as a channel complex. These studies prompt future investigation of the role of ClC-4 in renal function in health and in Dent's disease. Future studies will assess whether the severity of Dent's disease relates not only to the impact of particular mutations on ClC-5 but also on the consequences of those mutations on the functional expression of ClC-4.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M304357200</identifier><identifier>PMID: 12746443</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Caco-2 Cells ; Cells, Cultured ; Chloride Channels - deficiency ; Chloride Channels - genetics ; Chloride Channels - physiology ; CHO Cells ; Cricetinae ; DNA, Antisense - genetics ; Endosomes - chemistry ; Endosomes - metabolism ; Epithelial Cells - metabolism ; Fluorescent Antibody Technique ; Gene Expression ; Humans ; Hydrogen-Ion Concentration ; Immunosorbent Techniques ; Kidney Calculi - genetics ; Kidney Tubules, Proximal - chemistry ; Kidney Tubules, Proximal - metabolism ; Kidney Tubules, Proximal - ultrastructure ; Mice ; Mice, Knockout ; Microscopy, Confocal ; Microscopy, Electron ; Mutation ; Proteinuria - genetics ; Rats ; Receptors, Transferrin - metabolism ; Transfection</subject><ispartof>The Journal of biological chemistry, 2003-08, Vol.278 (31), p.29267-29277</ispartof><rights>2003 © 2003 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c506t-cb09fbf18f44ad8393e0416accf4997271879a6669278b8531e4f25f89d895563</citedby><cites>FETCH-LOGICAL-c506t-cb09fbf18f44ad8393e0416accf4997271879a6669278b8531e4f25f89d895563</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12746443$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mohammad-Panah, Raha</creatorcontrib><creatorcontrib>Harrison, Rene</creatorcontrib><creatorcontrib>Dhani, Sonja</creatorcontrib><creatorcontrib>Ackerley, Cameron</creatorcontrib><creatorcontrib>Huan, Ling-Jun</creatorcontrib><creatorcontrib>Wang, Yanchun</creatorcontrib><creatorcontrib>Bear, Christine E.</creatorcontrib><title>The Chloride Channel ClC-4 Contributes to Endosomal Acidification and Trafficking</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>Mutations in the gene coding for the chloride channel ClC-5 cause Dent's disease, a disease associated with proteinuria and renal stones. Studies in ClC-5 knockout mice suggest that this phenotype is related to defective endocytosis of low molecular weight proteins and membrane proteins by the renal proximal tubule. In this study, confocal micrographs of proximal tubules and cultured epithelial cells revealed that the related protein ClC-4 is expressed in endosomal membranes suggesting that this channel may also contribute to the function of this organelle. In support of this hypothesis, specific disruption of endogenous ClC-4 expression by transfection of ClC-4 antisense cDNA acidified endosomal pH and altered transferrin trafficking in cultured epithelial cells to the same extent as the specific disruption of ClC-5. Both channels can be co-immunoprecipitated, arguing that they may partially contribute to endosomal function as a channel complex. These studies prompt future investigation of the role of ClC-4 in renal function in health and in Dent's disease. Future studies will assess whether the severity of Dent's disease relates not only to the impact of particular mutations on ClC-5 but also on the consequences of those mutations on the functional expression of ClC-4.</description><subject>Animals</subject><subject>Caco-2 Cells</subject><subject>Cells, Cultured</subject><subject>Chloride Channels - deficiency</subject><subject>Chloride Channels - genetics</subject><subject>Chloride Channels - physiology</subject><subject>CHO Cells</subject><subject>Cricetinae</subject><subject>DNA, Antisense - genetics</subject><subject>Endosomes - chemistry</subject><subject>Endosomes - metabolism</subject><subject>Epithelial Cells - metabolism</subject><subject>Fluorescent Antibody Technique</subject><subject>Gene Expression</subject><subject>Humans</subject><subject>Hydrogen-Ion Concentration</subject><subject>Immunosorbent Techniques</subject><subject>Kidney Calculi - genetics</subject><subject>Kidney Tubules, Proximal - chemistry</subject><subject>Kidney Tubules, Proximal - metabolism</subject><subject>Kidney Tubules, Proximal - ultrastructure</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Microscopy, Confocal</subject><subject>Microscopy, Electron</subject><subject>Mutation</subject><subject>Proteinuria - genetics</subject><subject>Rats</subject><subject>Receptors, Transferrin - metabolism</subject><subject>Transfection</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkEtLHEEQgBtR4kZz9RjmILnN2q_px1EGTQRDCGzAW9PTD6fNTLd2zyb4723ZBU9iXaooviqqPgDOEFwjyOnFw2DWPwmkpOMYwgOwQlCQlnTo7hCsIMSolbgTx-BzKQ-wBpXoEzhGmFNGKVmB35vRNf04pRzsa6FjdFPTT31Lmz7FJYdhu7jSLKm5ijaVNOupuTTBBh-MXkKKjY622WTta-NviPen4Mjrqbgv-3wC_lxfbfof7e2v7zf95W1rOsiW1gxQ-sEj4SnVVhBJHKSIaWM8lZJjjgSXmjEmMReD6Ahy1OPOC2mF7DpGTsC33d7HnJ62rixqDsW4adLRpW1RnFDJBMEfgkiI6gWRCq53oMmplOy8esxh1vlZIahebatqW73ZrgNf95u3w-zsG77XW4HzHTCG-_F_yE4NIZnRzao-pQhSWGLGKyZ2mKu-_gWXVTHBReNsHTGLsim8d8IL87WXdA</recordid><startdate>20030801</startdate><enddate>20030801</enddate><creator>Mohammad-Panah, Raha</creator><creator>Harrison, Rene</creator><creator>Dhani, Sonja</creator><creator>Ackerley, Cameron</creator><creator>Huan, Ling-Jun</creator><creator>Wang, Yanchun</creator><creator>Bear, Christine E.</creator><general>Elsevier Inc</general><general>American Society for Biochemistry and Molecular Biology</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>20030801</creationdate><title>The Chloride Channel ClC-4 Contributes to Endosomal Acidification and Trafficking</title><author>Mohammad-Panah, Raha ; Harrison, Rene ; Dhani, Sonja ; Ackerley, Cameron ; Huan, Ling-Jun ; Wang, Yanchun ; Bear, Christine E.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c506t-cb09fbf18f44ad8393e0416accf4997271879a6669278b8531e4f25f89d895563</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>Animals</topic><topic>Caco-2 Cells</topic><topic>Cells, Cultured</topic><topic>Chloride Channels - deficiency</topic><topic>Chloride Channels - genetics</topic><topic>Chloride Channels - physiology</topic><topic>CHO Cells</topic><topic>Cricetinae</topic><topic>DNA, Antisense - genetics</topic><topic>Endosomes - chemistry</topic><topic>Endosomes - metabolism</topic><topic>Epithelial Cells - metabolism</topic><topic>Fluorescent Antibody Technique</topic><topic>Gene Expression</topic><topic>Humans</topic><topic>Hydrogen-Ion Concentration</topic><topic>Immunosorbent Techniques</topic><topic>Kidney Calculi - genetics</topic><topic>Kidney Tubules, Proximal - chemistry</topic><topic>Kidney Tubules, Proximal - metabolism</topic><topic>Kidney Tubules, Proximal - ultrastructure</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Microscopy, Confocal</topic><topic>Microscopy, Electron</topic><topic>Mutation</topic><topic>Proteinuria - genetics</topic><topic>Rats</topic><topic>Receptors, Transferrin - metabolism</topic><topic>Transfection</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mohammad-Panah, Raha</creatorcontrib><creatorcontrib>Harrison, Rene</creatorcontrib><creatorcontrib>Dhani, Sonja</creatorcontrib><creatorcontrib>Ackerley, Cameron</creatorcontrib><creatorcontrib>Huan, Ling-Jun</creatorcontrib><creatorcontrib>Wang, Yanchun</creatorcontrib><creatorcontrib>Bear, Christine E.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mohammad-Panah, Raha</au><au>Harrison, Rene</au><au>Dhani, Sonja</au><au>Ackerley, Cameron</au><au>Huan, Ling-Jun</au><au>Wang, Yanchun</au><au>Bear, Christine E.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The Chloride Channel ClC-4 Contributes to Endosomal Acidification and Trafficking</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2003-08-01</date><risdate>2003</risdate><volume>278</volume><issue>31</issue><spage>29267</spage><epage>29277</epage><pages>29267-29277</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>Mutations in the gene coding for the chloride channel ClC-5 cause Dent's disease, a disease associated with proteinuria and renal stones. 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| subjects | Animals Caco-2 Cells Cells, Cultured Chloride Channels - deficiency Chloride Channels - genetics Chloride Channels - physiology CHO Cells Cricetinae DNA, Antisense - genetics Endosomes - chemistry Endosomes - metabolism Epithelial Cells - metabolism Fluorescent Antibody Technique Gene Expression Humans Hydrogen-Ion Concentration Immunosorbent Techniques Kidney Calculi - genetics Kidney Tubules, Proximal - chemistry Kidney Tubules, Proximal - metabolism Kidney Tubules, Proximal - ultrastructure Mice Mice, Knockout Microscopy, Confocal Microscopy, Electron Mutation Proteinuria - genetics Rats Receptors, Transferrin - metabolism Transfection |
| title | The Chloride Channel ClC-4 Contributes to Endosomal Acidification and Trafficking |
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