Chloride anion exchanger explained

Chloride anion exchanger, also known as down-regulated in adenoma (protein DRA), is a protein that in humans is encoded by the SLC26A3 gene.^[1]

Function

Protein DRA is a membrane protein in intestinal cells. It is an anion exchanger and a member of the sulfate anion transporter (SAT) family. It mediates chloride and bicarbonate exchange and additionally transports sulfate and other anions at the apical membrane, part of the plasma membrane of enterocytes. It is different from the anion exchanger that present in erythrocytes, renal tubule, and several other tissues.^[2]

The protein encoded by this gene is a transmembrane glycoprotein that functions as a sulfate transporter. It is localized to the mucosa of the lower intestinal tract, particularly to the apical membrane of columnar epithelium and some goblet cells, and is instrumental in chloride reuptake, aiding in the creation of an osmotic gradient for resorption of fluid from the lumen of the intestine.^[3]

Clinical significance

Mutations in this gene have been associated with congenital chloride diarrhoea, a treatable disease.

The congenital absence of this membrane protein results in an autosomal recessive disorder called congenital chloridorrhea or congenital chloride diarrhea (CLD).^[4]

See also

• Solute carrier family

Further reading

• Sandal NN, Marcker KA . Similarities between a soybean nodulin, Neurospora crassa sulphate permease II and a putative human tumour suppressor . Trends in Biochemical Sciences . 19 . 1 . 19 . January 1994 . 8140616 . 10.1016/0968-0004(94)90168-6 .
• Markovich D . Physiological roles and regulation of mammalian sulfate transporters . Physiological Reviews . 81 . 4 . 1499–533 . October 2001 . 11581495 . 10.1152/physrev.2001.81.4.1499. 30942862 .
• Mäkelä S, Kere J, Holmberg C, Höglund P . SLC26A3 mutations in congenital chloride diarrhea . Human Mutation . 20 . 6 . 425–38 . December 2002 . 12442266 . 10.1002/humu.10139 . 2450225 . free .
• Schweinfest CW, Henderson KW, Suster S, Kondoh N, Papas TS . Identification of a colon mucosa gene that is down-regulated in colon adenomas and adenocarcinomas . Proceedings of the National Academy of Sciences of the United States of America . 90 . 9 . 4166–70 . May 1993 . 7683425 . 46467 . 10.1073/pnas.90.9.4166 . 1993PNAS...90.4166S . free .
• Taguchi T, Testa JR, Papas TS, Schweinfest C . Localization of a candidate colon tumor-suppressor gene (DRA) to 7q22-q31.1 by fluorescence in situ hybridization . Genomics . 20 . 1 . 146–7 . March 1994 . 8020951 . 10.1006/geno.1994.1148 .
• Höglund P, Haila S, Socha J, Tomaszewski L, Saarialho-Kere U, Karjalainen-Lindsberg ML, Airola K, Holmberg C, de la Chapelle A, Kere J . Mutations of the Down-regulated in adenoma (DRA) gene cause congenital chloride diarrhoea . Nature Genetics . 14 . 3 . 316–9 . November 1996 . 8896562 . 10.1038/ng1196-316 . 1725926 .
• Byeon MK, Frankel A, Papas TS, Henderson KW, Schweinfest CW . Human DRA functions as a sulfate transporter in Sf9 insect cells . Protein Expression and Purification . 12 . 1 . 67–74 . February 1998 . 9473459 . 10.1006/prep.1997.0809 .
• Höglund P, Haila S, Gustavson KH, Taipale M, Hannula K, Popinska K, Holmberg C, Socha J, de la Chapelle A, Kere J . Clustering of private mutations in the congenital chloride diarrhea/down-regulated in adenoma gene . Human Mutation . 11 . 4 . 321–7 . 1998 . 9554749 . 10.1002/(SICI)1098-1004(1998)11:4<321::AID-HUMU10>3.0.CO;2-A . 39309679 .
• Antalis TM, Reeder JA, Gotley DC, Byeon MK, Walsh MD, Henderson KW, Papas TS, Schweinfest CW . Down-regulation of the down-regulated in adenoma (DRA) gene correlates with colon tumor progression . Clinical Cancer Research . 4 . 8 . 1857–63 . August 1998 . 9717812 .
• Höglund P, Auranen M, Socha J, Popinska K, Nazer H, Rajaram U, Al Sanie A, Al-Ghanim M, Holmberg C, de la Chapelle A, Kere J . Genetic background of congenital chloride diarrhea in high-incidence populations: Finland, Poland, and Saudi Arabia and Kuwait . American Journal of Human Genetics . 63 . 3 . 760–8 . September 1998 . 9718329 . 1377387 . 10.1086/301998 .
• Lohi H, Kujala M, Kerkelä E, Saarialho-Kere U, Kestilä M, Kere J . Mapping of five new putative anion transporter genes in human and characterization of SLC26A6, a candidate gene for pancreatic anion exchanger . Genomics . 70 . 1 . 102–12 . November 2000 . 11087667 . 10.1006/geno.2000.6355 .
• Höglund P, Sormaala M, Haila S, Socha J, Rajaram U, Scheurlen W, Sinaasappel M, de Jonge H, Holmberg C, Yoshikawa H, Kere J . Identification of seven novel mutations including the first two genomic rearrangements in SLC26A3 mutated in congenital chloride diarrhea . Human Mutation . 18 . 3 . 233–42 . September 2001 . 11524734 . 10.1002/humu.1179 . 19422198 . free .
• Lohi H, Kujala M, Makela S, Lehtonen E, Kestila M, Saarialho-Kere U, Markovich D, Kere J . Functional characterization of three novel tissue-specific anion exchangers SLC26A7, -A8, and -A9 . The Journal of Biological Chemistry . 277 . 16 . 14246–54 . April 2002 . 11834742 . 10.1074/jbc.M111802200 . free .
• Lamprecht G, Heil A, Baisch S, Lin-Wu E, Yun CC, Kalbacher H, Gregor M, Seidler U . The down regulated in adenoma (dra) gene product binds to the second PDZ domain of the NHE3 kinase A regulatory protein (E3KARP), potentially linking intestinal Cl-/HCO3- exchange to Na+/H+ exchange . Biochemistry . 41 . 41 . 12336–42 . October 2002 . 12369822 . 10.1021/bi0259103 .
• Chernova MN, Jiang L, Shmukler BE, Schweinfest CW, Blanco P, Freedman SD, Stewart AK, Alper SL . Acute regulation of the SLC26A3 congenital chloride diarrhoea anion exchanger (DRA) expressed in Xenopus oocytes . The Journal of Physiology . 549 . Pt 1 . 3–19 . May 2003 . 12651923 . 2342915 . 10.1113/jphysiol.2003.039818 .

Notes and References

1. Web site: Entrez Gene: SLC26A3 solute carrier family 26, member 3.
2. Sterling D, Brown NJ, Supuran CT, Casey JR . The functional and physical relationship between the DRA bicarbonate transporter and carbonic anhydrase II . American Journal of Physiology. Cell Physiology . 283 . 5 . C1522-9 . November 2002 . 12372813 . 10.1152/ajpcell.00115.2002 .
3. Singla A, Kumar A, Priyamvada S, Tahniyath M, Saksena S, Gill RK, Alrefai WA, Dudeja PK . LPA stimulates intestinal DRA gene transcription via LPA2 receptor, PI3K/AKT, and c-Fos-dependent pathway . American Journal of Physiology. Gastrointestinal and Liver Physiology . 302 . 6 . G618-27 . March 2012 . 22159277 . 10.1152/ajpgi.00172.2011 . 3311307 .
4. Alrefai WA, Wen X, Jiang W, Katz JP, Steinbrecher KA, Cohen MB, Williams IR, Dudeja PK, Wu GD . Molecular cloning and promoter analysis of downregulated in adenoma (DRA) . American Journal of Physiology. Gastrointestinal and Liver Physiology . 293 . 5 . G923-34 . November 2007 . 17761837 . 10.1152/ajpgi.00029.2007 .