Mouse Down-regulated in Adenoma (DRA) Is an Intestinal Cl−/HCO3− 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−/HCO3− 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−/CHO3− exchange activity. Removal of extracellular Cl− from medium containing HCO3− caused a rapid intracellular alkalinization, whereas the intracellular pH increase following Cl−removal from HCO3−-free medium was reduced greater than 7-fold. The intracellular alkalinization in Cl−-free, HCO3−-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−/HCO3− 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. Mutations in human DRA cause congenital chloride diarrhea, thereby raising the possibility that it functions as a Cl−/HCO3− 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−/CHO3− exchange activity. Removal of extracellular Cl− from medium containing HCO3− caused a rapid intracellular alkalinization, whereas the intracellular pH increase following Cl−removal from HCO3−-free medium was reduced greater than 7-fold. The intracellular alkalinization in Cl−-free, HCO3−-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−/HCO3− 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. Human DRA, 1The abbreviations used are: DRA, down-regulated in adenoma; mDRA, mouse DRA; hDRA, human DRA; CLD, congenital chloride diarrhea; NHE, Na+/H+ exchanger; NHE3, NHE isoform 3; AE, anion exchanger; AE2, AE isoform 2; DIDS, diisothiocyanostilbene disulfonic acid; RACE, rapid amplification of cDNA ends; PCR, polymerase chain reaction; kb, kilobase(s); Nhe3 +/+ and Nhe3 −/−, NHE3 wild-type and homozygous mutant mice, respectively 1The abbreviations used are: DRA, down-regulated in adenoma; mDRA, mouse DRA; hDRA, human DRA; CLD, congenital chloride diarrhea; NHE, Na+/H+ exchanger; NHE3, NHE isoform 3; AE, anion exchanger; AE2, AE isoform 2; DIDS, diisothiocyanostilbene disulfonic acid; RACE, rapid amplification of cDNA ends; PCR, polymerase chain reaction; kb, kilobase(s); Nhe3 +/+ and Nhe3 −/−, NHE3 wild-type and homozygous mutant mice, respectively cloned from a colon cDNA subtraction library, is expressed in the normal colon but not in most adenocarcinomas, thus the termDown-Regulated in Adenoma (1Schweinfest C.W. Henderson K.W. Suster S. Kondoh N. Papas T.S. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 4166-4170Crossref PubMed Scopus (192) Google Scholar). Although it was originally proposed as a candidate tumor suppressor protein, there is only a slight increase in the incidence of intestinal cancer among individuals carrying mutations in the gene (2Hemminki A. Hoglund P. Pukkala E. Salovaara R. Jarvinen H. Norio R. Aaltonen L.A. PubMed Scopus Google Scholar). that DRA is to the A. A. A. A. PubMed Scopus Google and PubMed Google and that it a activity expressed in PubMed Scopus Google or A. Papas T.S. Henderson K.W. C.W. PubMed Scopus Google Scholar). is is the of of with congenital chloride there is of a in Cl−/HCO3− exchange in the and colon P. PubMed Scopus Google PubMed Scopus Google PubMed Scopus Google that the was caused by mutations in gene P. S. U. A. PubMed Scopus Google P. H. U. A. A. PubMed Scopus Google Scholar). that DRA a in Cl− in the with this Hoglund P. S. A. Google that DRA Cl− expressed These not a of the Cl− was Cl−/HCO3− colon is a NaCl in the and of this activity to by coupled Na+/H+ and Cl−/HCO3− exchange R. E. H. Google 1993; Google PubMed Scopus Google Scholar). Na+/H+ and NHE3, expressed of epithelial in the small and colon Google P. PubMed Scopus Google Scholar). in mice lacking NHE3 P. PubMed Scopus Google but not in mice lacking P. PubMed Scopus Google Scholar). These that NHE3 is the Na+/H+ exchanger to NaCl coupled Na+/H+ and the of the anion exchanger in NaCl is The Cl−/HCO3− exchanger is expressed the PubMed Google and was by in from A. P. PubMed Google Scholar). it is that this isoform at in the Cl−/HCO3− exchange activity in small intestine. the membrane of in colonic epithelial not and that it is expressed in epithelial of the A. PubMed Google Google and PubMed Scopus Google Scholar). the in Cl−/HCO3− exchange in that is not the Cl−/HCO3− exchanger in the and is expressed in colon and cecum and to a in the small PubMed Scopus Google P. S. U. A. PubMed Scopus Google and is to the of colonic and the of the Henderson K.W. Suster S. Papas T.S. C.W. Google Scholar). is to that it the Cl−/HCO3− exchange activity that in normal colon PubMed Scopus Google Proc. PubMed Scopus Google and to in P. PubMed Scopus Google PubMed Scopus Google PubMed Scopus Google Scholar). To test the hypothesis that DRA Cl−/HCO3− we cloned and expressed mouse that mDRA, is to of the AE Cl−/HCO3− exchanger Na+-independent, electroneutral Cl−/HCO3− exchange expressed in mammalian cells. When in the of of DRA and the results of this suggest that DRA is the Cl−/HCO3− exchanger of the intestinal chloride is by containing high of Cl− and of HCO3− N. PubMed Scopus Google Scholar). the of and N. PubMed Scopus Google from a in intestinal Cl− P. PubMed Scopus Google PubMed Scopus Google PubMed Scopus Google Scholar). Human that mutations in the DRA gene P. S. U. A. PubMed Scopus Google P. H. U. A. A. PubMed Scopus Google and expression that DRA of and Cl− PubMed Scopus Google Hoglund P. S. A. Google and that the functions as a exchanger A. A. A. A. PubMed Scopus Google Google Scholar). the activity of the was not that Cl−/HCO3− exchange was in the P. PubMed Scopus Google and colon PubMed Scopus Google PubMed Scopus Google of but not the possibility that DRA to this as of a coupled was to test the hypothesis that DRA functions as a Cl−/HCO3− this we analyzed the activity of the in HEK 293 cells. of the by removal of extracellular Cl− in the of extracellular HCO3− to a rapid alkalinization of DRA, and intracellular pH Cl− was to the extracellular medium. removal of Cl− was HCO3−-free the of increase in intracellular pH was sharply These show that HCO3− is the in to Cl− and that the is extracellular Cl− is The alkalinization Cl− removal in the of HCO3− was not by extracellular Na+ or by depolarization of the the of we that mDRA as Cl−/HCO3− of alkalinization that Cl−removal in the of extracellular HCO3− is and the possibility that in the extracellular as by is a this as there is that at a PubMed Google Scholar). These and the that DRA of and chloride expressed in PubMed Scopus Google Hoglund P. S. A. Google suggest that the anion of its extracellular is possibility is by the of PubMed Scopus Google that Cl− in membrane from human colon Cl−/HCO3− that and of and that the colonic Cl−/HCO3− exchanger as the from expression and with the possibility that the of DRA not only the of Cl− from the intestinal but as of the intracellular alkalinization that in the of extracellular Cl− and HCO3− was that of Cl− not to the rapid of intracellular pH that was in HCO3−-containing medium. The this is it that the intracellular anion a than was the it not extracellular was by high HCO3− at the intracellular a exchanger in from the intestinal as it the of HCO3− in exchange Cl− and in the of the but sharply the of those to the of that by DRA and the extracellular and intracellular anion and of expressed in to by mm PubMed Scopus Google Hoglund P. S. A. Google Scholar). Cl− was from the extracellular medium containing the alkalinization of HEK 293 by only The in the of the mDRA and the in to in the expression the of is greater expressed in PubMed Google than in HEK 293 PubMed Google Scholar). the only addition of and not that as a of of the that Cl−/HCO3− exchange is in and colon of P. PubMed Scopus Google PubMed Scopus Google PubMed Scopus Google Although it that Cl−/HCO3− exchange in L.A. PubMed Scopus Google P. PubMed Scopus Google that the in HCO3− in the of with HCO3−-containing was not to HCO3− but to and of as by in the as HCO3− of and of the colon of and PubMed Scopus Google to the that Cl−/HCO3− exchange was in and PubMed Scopus Google that Cl− and HCO3− in the of were by and of in to the coupled in normal with of Cl−/HCO3− exchange in the intestinal The of Cl−/HCO3− exchange in and colon of P. PubMed Scopus Google PubMed Scopus Google PubMed Scopus Google the that mutations in gene cause P. S. U. A. PubMed Scopus Google P. H. U. A. A. PubMed Scopus Google the of DRA to the in colonic Henderson K.W. Suster S. Papas T.S. C.W. Google and that DRA is a that DRA is the Cl−/HCO3− exchanger that Cl− by and colonic epithelial of DRA mRNA in the colon of mice lacking the NHE3 Na+/H+ exchanger that DRA is a of the that the of fluid and in a The of NHE3 a intestinal in and of the intestinal P. PubMed Scopus Google Scholar). The that increase in the of intestinal with of the colonic H+,K+-ATPase and activity of the epithelial Na+ channel in the colon P. PubMed Scopus Google Scholar). is in Nhe3 mice, the of the H+,K+-ATPase PubMed Google PubMed Scopus Google P. PubMed Scopus Google and the Na+ channel PubMed Scopus Google N. PubMed Scopus Google with that of K+ mediate the exchange of extracellular Na+ and K+ intracellular thereby Na+ and K+ and the of as not a and the of Cl− that in the the of and fluid that of the in the small the colon absorb a of fluid and extracellular Cl− and intracellular DRA Cl− thereby the to absorb Na+ and K+ and to absorb HCO3− of with of following absorption. the of it that the of and fluid in the colon of Nhe3 mice is to the coupled of the DRA Cl−/HCO3− the colonic K+ and the epithelial Na+ wild-type mice by the coupled of DRA and expression of mRNA in cecum and colon of Nhe3 mice, but not in colon high levels of Na+ channel activity and colonic H+,K+-ATPase expression P. PubMed Scopus Google Scholar). the that HCO3− the coupled with by the up-regulated is by The in of the and DRA suggest that expressed at lower levels than DRA in of the intestine. The of in the is is that its expression is to it mediate HCO3− from the this is the it to in the membrane the of the show that DRA functions as a Cl−/HCO3− exchanger and the possibility that it Cl− from the intestinal When the results of and the human P. PubMed Scopus Google PubMed Scopus Google PubMed Scopus Google P. S. U. A. PubMed Scopus Google P. H. U. A. A. PubMed Scopus Google suggest that DRA is not of the Cl−/HCO3− exchange in colon and in of the of Cl− in colonic PubMed Scopus Google DRA a in the of and fluid from the intestinal in to the of DRA is as in mammalian as it is in its in the colon mice that it from the of the of the Cl−/HCO3− is in at levels in of A. P. PubMed Google and is expressed the intestinal of PubMed Google and mouse is that the intestinal of is to mediate the of that in of the functions and the and of the DRA and the Cl−/HCO3− to a of the and in the intestinal Human DRA, 1The abbreviations used are: DRA, down-regulated in adenoma; mDRA, mouse DRA; hDRA, human DRA; CLD, congenital chloride diarrhea; NHE, Na+/H+ exchanger; NHE3, NHE isoform 3; AE, anion exchanger; AE2, AE isoform 2; DIDS, diisothiocyanostilbene disulfonic acid; RACE, rapid amplification of cDNA ends; PCR, polymerase chain reaction; kb, kilobase(s); Nhe3 +/+ and Nhe3 −/−, NHE3 wild-type and homozygous mutant mice, respectively 1The abbreviations used are: DRA, down-regulated in adenoma; mDRA, mouse DRA; hDRA, human DRA; CLD, congenital chloride diarrhea; NHE, Na+/H+ exchanger; NHE3, NHE isoform 3; AE, anion exchanger; AE2, AE isoform 2; DIDS, diisothiocyanostilbene disulfonic acid; RACE, rapid amplification of cDNA ends; PCR, polymerase chain reaction; kb, kilobase(s); Nhe3 +/+ and Nhe3 −/−, NHE3 wild-type and homozygous mutant mice, respectively cloned from a colon cDNA subtraction library, is expressed in the normal colon but not in most adenocarcinomas, thus the termDown-Regulated in Adenoma (1Schweinfest C.W. Henderson K.W. Suster S. Kondoh N. Papas T.S. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 4166-4170Crossref PubMed Scopus (192) Google Scholar). Although it was originally proposed as a candidate tumor suppressor protein, there is only a slight increase in the incidence of intestinal cancer among individuals carrying mutations in the gene (2Hemminki A. Hoglund P. Pukkala E. Salovaara R. Jarvinen H. Norio R. Aaltonen L.A. PubMed Scopus Google Scholar). that DRA is to the A. A. A. A. PubMed Scopus Google and PubMed Google and that it a activity expressed in PubMed Scopus Google or A. Papas T.S. Henderson K.W. C.W. PubMed Scopus Google Scholar). is is the of of with congenital chloride there is of a in Cl−/HCO3− exchange in the and colon P. PubMed Scopus Google PubMed Scopus Google PubMed Scopus Google that the was caused by mutations in gene P. S. U. A. PubMed Scopus Google P. H. U. A. A. PubMed Scopus Google Scholar). that DRA a in Cl− in the with this Hoglund P. S. A. Google that DRA Cl− expressed These not a of the Cl− was Cl−/HCO3− The colon is a NaCl in the and of this activity to by coupled Na+/H+ and Cl−/HCO3− exchange R. E. H. Google 1993; Google PubMed Scopus Google Scholar). Na+/H+ and NHE3, expressed of epithelial in the small and colon Google P. PubMed Scopus Google Scholar). in mice lacking NHE3 P. PubMed Scopus Google but not in mice lacking P. PubMed Scopus Google Scholar). These that NHE3 is the Na+/H+ exchanger to NaCl coupled Na+/H+ and the of the anion exchanger in NaCl is The Cl−/HCO3− exchanger is expressed the PubMed Google and was by in from A. P. PubMed Google Scholar). it is that this isoform at in the Cl−/HCO3− exchange activity in small intestine. the membrane of in colonic epithelial not and that it is expressed in epithelial of the A. PubMed Google Google and PubMed Scopus Google Scholar). the in Cl−/HCO3− exchange in that is not the Cl−/HCO3− exchanger in the and DRA is expressed in colon and cecum and to a in the small PubMed Scopus Google P. S. U. A. PubMed Scopus Google and is to the of colonic and the of the Henderson K.W. Suster S. Papas T.S. C.W. Google Scholar). is to that it the Cl−/HCO3− exchange activity that in normal colon PubMed Scopus Google Proc. PubMed Scopus Google and to in P. PubMed Scopus Google PubMed Scopus Google PubMed Scopus Google Scholar). To test the hypothesis that DRA Cl−/HCO3− we cloned and expressed mouse that mDRA, is to of the AE Cl−/HCO3− exchanger Na+-independent, electroneutral Cl−/HCO3− exchange expressed in mammalian cells. When in the of of DRA and the results of this suggest that DRA is the Cl−/HCO3− exchanger of the intestinal chloride is by containing high of Cl− and of HCO3− N. PubMed Scopus Google Scholar). the of and N. PubMed Scopus Google from a in intestinal Cl− P. PubMed Scopus Google PubMed Scopus Google PubMed Scopus Google Scholar). Human that mutations in the DRA gene P. S. U. A. PubMed Scopus Google P. H. U. A. A. PubMed Scopus Google and expression that DRA of and Cl− PubMed Scopus Google Hoglund P. S. A. Google and that the functions as a exchanger A. A. A. A. PubMed Scopus Google Google Scholar). the activity of the was not that Cl−/HCO3− exchange was in the P. PubMed Scopus Google and colon PubMed Scopus Google PubMed Scopus Google of but not the possibility that DRA to this as of a coupled was to test the hypothesis that DRA functions as a Cl−/HCO3− this we analyzed the activity of the in HEK 293 cells. of the by removal of extracellular Cl− in the of extracellular HCO3− to a rapid alkalinization of DRA, and intracellular pH Cl− was to the extracellular medium. removal of Cl− was HCO3−-free the of increase in intracellular pH was sharply These show that HCO3− is the in to Cl− and that the is extracellular Cl− is The alkalinization Cl− removal in the of HCO3− was not by extracellular Na+ or by depolarization of the the of we that mDRA as Cl−/HCO3− of alkalinization that Cl−removal in the of extracellular HCO3− is and the possibility that in the extracellular as by is a this as there is that at a PubMed Google Scholar). These and the that DRA of and chloride expressed in PubMed Scopus Google Hoglund P. S. A. Google suggest that the anion of its extracellular is possibility is by the of PubMed Scopus Google that Cl− in membrane from human colon Cl−/HCO3− that and of and that the colonic Cl−/HCO3− exchanger as the from expression and with the possibility that the of DRA not only the of Cl− from the intestinal but as of the intracellular alkalinization that in the of extracellular Cl− and HCO3− was that of Cl− not to the rapid of intracellular pH that was in HCO3−-containing medium. The this is it that the intracellular anion a than was the it not extracellular was by high HCO3− at the intracellular a exchanger in from the intestinal as it the of HCO3− in exchange Cl− and in the of the but sharply the of those to the of that by DRA and the extracellular and intracellular anion and of expressed in to by mm PubMed Scopus Google Hoglund P. S. A. Google Scholar). Cl− was from the extracellular medium containing the alkalinization of HEK 293 by only The in the of the mDRA and the in to in the expression the of is greater expressed in PubMed Google than in HEK 293 PubMed Google Scholar). the only addition of and not that as a of of the that Cl−/HCO3− exchange is in and colon of P. PubMed Scopus Google PubMed Scopus Google PubMed Scopus Google Although it that Cl−/HCO3− exchange in L.A. PubMed Scopus Google P. PubMed Scopus Google that the in HCO3− in the of with HCO3−-containing was not to HCO3− but to and of as by in the as HCO3− of and of the colon of and PubMed Scopus Google to the that Cl−/HCO3− exchange was in and PubMed Scopus Google that Cl− and HCO3− in the of were by and of in to the coupled in normal with of Cl−/HCO3− exchange in the intestinal The of Cl−/HCO3− exchange in and colon of P. PubMed Scopus Google PubMed Scopus Google PubMed Scopus Google the that mutations in gene cause P. S. U. A. PubMed Scopus Google P. H. U. A. A. PubMed Scopus Google the of DRA to the in colonic Henderson K.W. Suster S. Papas T.S. C.W. Google and that DRA is a that DRA is the Cl−/HCO3− exchanger that Cl− by and colonic epithelial of DRA mRNA in the colon of mice lacking the NHE3 Na+/H+ exchanger that DRA is a of the that the of fluid and in a The of NHE3 a intestinal in and of the intestinal P. PubMed Scopus Google Scholar). The that increase in the of intestinal with of the colonic H+,K+-ATPase and activity of the epithelial Na+ channel in the colon P. PubMed Scopus Google Scholar). is in Nhe3 mice, the of the H+,K+-ATPase PubMed Google PubMed Scopus Google P. PubMed Scopus Google and the Na+ channel PubMed Scopus Google N. PubMed Scopus Google with that of K+ mediate the exchange of extracellular Na+ and K+ intracellular thereby Na+ and K+ and the of as not a and the of Cl− that in the the of and fluid that of the in the small the colon absorb a of fluid and extracellular Cl− and intracellular DRA Cl− thereby the to absorb Na+ and K+ and to absorb HCO3− of with of following absorption. the of it that the of and fluid in the colon of Nhe3 mice is to the coupled of the DRA Cl−/HCO3− the colonic K+ and the epithelial Na+ wild-type mice by the coupled of DRA and expression of mRNA in cecum and colon of Nhe3 mice, but not in colon high levels of Na+ channel activity and colonic H+,K+-ATPase expression P. PubMed Scopus Google Scholar). the that HCO3− the coupled with by the up-regulated is by The in of the and DRA suggest that expressed at lower levels than DRA in of the intestine. The of in the is is that its expression is to it mediate HCO3− from the this is the it to in the membrane the of the show that DRA functions as a Cl−/HCO3− exchanger and the possibility that it Cl− from the intestinal When the results of and the human P. PubMed Scopus Google PubMed Scopus Google PubMed Scopus Google P. S. U. A. PubMed Scopus Google P. H. U. A. A. PubMed Scopus Google suggest that DRA is not of the Cl−/HCO3− exchange in colon and in of the of Cl− in colonic PubMed Scopus Google DRA a in the of and fluid from the intestinal in to the of DRA is as in mammalian as it is in its in the colon mice that it from the of the of the Cl−/HCO3− is in at levels in of A. P. PubMed Google and is expressed the intestinal of PubMed Google and mouse is that the intestinal of is to mediate the of that in of the functions and the and of the DRA and the Cl−/HCO3− to a of the and in the intestinal chloride is by containing high of Cl− and of HCO3− N. PubMed Scopus Google Scholar). the of and N. PubMed Scopus Google from a in intestinal Cl− P. PubMed Scopus Google PubMed Scopus Google PubMed Scopus Google Scholar). Human that mutations in the DRA gene P. S. U. A. PubMed Scopus Google P. H. U. A. A. PubMed Scopus Google and expression that DRA of and Cl− PubMed Scopus Google Hoglund P. S. A. Google and that the functions as a exchanger A. A. A. A. PubMed Scopus Google Google Scholar). the activity of the was not that Cl−/HCO3− exchange was in the P. PubMed Scopus Google and colon PubMed Scopus Google PubMed Scopus Google of but not the possibility that DRA to this as of a coupled was to test the hypothesis that DRA functions as a Cl−/HCO3− exchanger. To this we analyzed the activity of the in HEK 293 cells. of the by removal of extracellular Cl− in the of extracellular HCO3− to a rapid alkalinization of DRA, and intracellular pH Cl− was to the extracellular medium. removal of Cl− was HCO3−-free the of increase in intracellular pH was sharply These show that HCO3− is the in to Cl− and that the is extracellular Cl− is The alkalinization Cl− removal in the of HCO3− was not by extracellular Na+ or by depolarization of the the of we that mDRA as Cl−/HCO3− exchanger. The of alkalinization that Cl−removal in the of extracellular HCO3− is and the possibility that in the extracellular as by is a this as there is that at a PubMed Google Scholar). These and the that DRA of and chloride expressed in PubMed Scopus Google Hoglund P. S. A. Google suggest that the anion of its extracellular is possibility is by the of PubMed Scopus Google that Cl− in membrane from human colon Cl−/HCO3− that and of and that the colonic Cl−/HCO3− exchanger as the from expression and with the possibility that the of DRA not only the of Cl− from the intestinal but as of the intracellular alkalinization that in the of extracellular Cl− and HCO3− was that of Cl− not to the rapid of intracellular pH that was in HCO3−-containing medium. The this is it that the intracellular anion a than was the it not extracellular was by high HCO3− at the intracellular a exchanger in from the intestinal as it the of HCO3− in exchange Cl− and in the of the but sharply the of those to the of that by DRA and the extracellular and intracellular anion The and of expressed in to by mm PubMed Scopus Google Hoglund P. S. A. Google Scholar). Cl− was from the extracellular medium containing the alkalinization of HEK 293 by only The in the of the mDRA and the in to in the expression the of is greater expressed in PubMed Google than in HEK 293 PubMed Google Scholar). the only addition of and not that as a of of the The that Cl−/HCO3− exchange is in and colon of P. PubMed Scopus Google PubMed Scopus Google PubMed Scopus Google Although it that Cl−/HCO3− exchange in L.A. PubMed Scopus Google P. PubMed Scopus Google that the in HCO3− in the of with HCO3−-containing was not to HCO3− but to and of as by in the as HCO3− of and of the colon of and PubMed Scopus Google to the that Cl−/HCO3− exchange was in and PubMed Scopus Google that Cl− and HCO3− in the of were by and of in to the coupled in normal with of Cl−/HCO3− exchange in the intestinal The of Cl−/HCO3− exchange in and colon of P. PubMed Scopus Google PubMed Scopus Google PubMed Scopus Google the that mutations in gene cause P. S. U. A. PubMed Scopus Google P. H. U. A. A. PubMed Scopus Google the of DRA to the in colonic Henderson K.W. Suster S. Papas T.S. C.W. Google and that DRA is a that DRA is the Cl−/HCO3− exchanger that Cl− by and colonic epithelial cells. The of DRA mRNA in the colon of mice lacking the NHE3 Na+/H+ exchanger that DRA is a of the that the of fluid and in a The of NHE3 a intestinal in and of the intestinal P. PubMed Scopus Google Scholar). The that increase in the of intestinal with of the colonic H+,K+-ATPase and activity of the epithelial Na+ channel in the colon P. PubMed Scopus Google Scholar). is in Nhe3 mice, the of the H+,K+-ATPase PubMed Google PubMed Scopus Google P. PubMed Scopus Google and the Na+ channel PubMed Scopus Google N. PubMed Scopus Google with that of K+ mediate the exchange of extracellular Na+ and K+ intracellular thereby Na+ and K+ and the of as not a and the of Cl− that in the the of and fluid that of the in the small the colon absorb a of fluid and extracellular Cl− and intracellular DRA Cl− thereby the to absorb Na+ and K+ and to absorb HCO3− of with of following absorption. the of it that the of and fluid in the colon of Nhe3 mice is to the coupled of the DRA Cl−/HCO3− the colonic K+ and the epithelial Na+ wild-type mice by the coupled of DRA and expression of mRNA in cecum and colon of Nhe3 mice, but not in colon high levels of Na+ channel activity and colonic H+,K+-ATPase expression P. PubMed Scopus Google Scholar). the that HCO3− the coupled with by the up-regulated is by The in of the and DRA suggest that expressed at lower levels than DRA in of the intestine. The of in the is is that its expression is to it mediate HCO3− from the this is the it to in the membrane the of the show that DRA functions as a Cl−/HCO3− exchanger and the possibility that it Cl− from the intestinal When the results of and the human P. PubMed Scopus Google PubMed Scopus Google PubMed Scopus Google P. S. U. A. PubMed Scopus Google P. H. U. A. A. PubMed Scopus Google suggest that DRA is not of the Cl−/HCO3− exchange in colon and in of the of Cl− in colonic PubMed Scopus Google DRA a in the of and fluid from the intestinal in to the of DRA is as in mammalian as it is in its in the colon mice that it from the of the of the Cl−/HCO3− is in at levels in of A. P. PubMed Google and is expressed the intestinal of PubMed Google and mouse is that the intestinal of is to mediate the of that in of the functions and the and of the DRA and the Cl−/HCO3− to a of the and in the intestinal