Mouse down-regulated in adenoma (DRA) is an intestinal Cl(-)/HCO(3)(-) exchanger and is up-regulated in colon of mice lacking the NHE3 Na(+)/H(+) exchanger.
Mutations in human DRA cause congenital chloride diarrhea, thereby raising the possibility that it functions as a Cl(-)/HCO(3)(-) exchanger. To test this hypothesis we cloned a cDNA encoding mouse DRA (mDRA) and analyzed its activity in cultured mammalian cells. When expressed in HEK 293 cells, mDRA conferred Na(+)-independent, electroneutral Cl(-)/CHO(3)(-) exchange activity. Removal of extracellular Cl(-) from medium containing HCO(3)(-) caused a rapid intracellular alkalinization, whereas the intracellular pH increase following Cl(-) removal from HCO(3)(-)-free medium was reduced greater than 7-fold. The intracellular alkalinization in Cl(-)-free, HCO(3)(-)-containing medium was unaffected by removal of extracellular Na(+) or by depolarization of the membrane by addition of 75 mM K(+) to the medium. Like human DRA mRNA, mDRA transcripts were expressed at high levels in cecum and colon and at lower levels in small intestine. The expression of mDRA mRNA was modestly up-regulated in the colon of mice lacking the NHE3 Na(+)/H(+) exchanger. These results show that DRA is a Cl(-)/HCO(3)(-) exchanger and suggest that it normally acts in concert with NHE3 to absorb NaCl and that in NHE3-deficient mice its activity is coupled with those of the sharply up-regulated colonic H(+),K(+)-ATPase and epithelial Na(+) channel to mediate electrolyte and fluid absorption.
Melvin
J E
JE
Center for Oral Biology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA.
Park
K
K
Richardson
L
L
Schultheis
P J
PJ
Shull
G E
GE
D000595:Amino Acid Sequence; D000818:Animals; D017920:Antiporters / Q000096:biosynthesis* / Q000235:genetics; D001483:Base Sequence; D001639:Bicarbonates / Q000378:metabolism*; D001692:Biological Transport; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics; D027963:Chloride-Bicarbonate Antiporters; D002712:Chlorides / Q000009:adverse effects / Q000378:metabolism*; D003001:Cloning, Molecular; D003106:Colon / Q000378:metabolism*; D018076:DNA, Complementary / Q000235:genetics; D003967:Diarrhea / Q000151:congenital; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D011994:Recombinant Proteins / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism*; D000076988:Sulfate Transporters; D015854:Up-Regulation
D017920:Antiporters; D001639:Bicarbonates; D002352:Carrier Proteins; D027963:Chloride-Bicarbonate Antiporters; D002712:Chlorides; D018076:DNA, Complementary; D008565:Membrane Proteins; D011994:Recombinant Proteins; C081011:SLC26A3 protein, human; C000613385:SLC9A3 protein, human; C489860:Slc26a3 protein, mouse; C000613386:Slc9a3 protein, mouse; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D000076988:Sulfate Transporters