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

Melvin, James E.; Park, Keerang; Richardson, Linda; Schultheis, Patrick J.; Shull, Gary E.

doi:10.1074/jbc.274.32.22855

Cited by 251 publications

(219 citation statements)

References 45 publications

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“…3, B-D). We conclude that gpSlc26a3 mediates predominantly electroneutral Cl Ϫ /HCO 3 Ϫ exchange, in concert with data reported for human SLC26A3 (8) and mouse Slc26a3 (1,17,26,28,31,58,59). However, functional data on microperfused isolated interlobular ducts suggests that Slc26a3-like, H 2 -DIDS-insensitive Cl Ϫ /HCO 3 Ϫ exchange constitutes only ϳ20% of apical Cl Ϫ /HCO 3 Ϫ exchange under alkaline load conditions (53).…”

Section: C297mentioning

confidence: 42%

“…Mouse and human Slc26a3-mediated Cl Ϫ /HCO 3 Ϫ exchange have been reported to be electrogenic (33,44) or electroneutral (1,8,31,59). We therefore measured electrical parameters of gpSlc26a3 expression.…”

Section: Molecular Cloning Of Slc26a3 Slc26a6 and Slc26a11 Cdnas Frmentioning

confidence: 99%

“…Moreover, mathematical modeling predicts a modest increase in ductal HCO 3 Ϫ secretion resulting from the presence of lumenal electrogenic anion exchange (49). In addition, numerous experiments have not detected electrogenicity of Cl Ϫ /HCO 3 Ϫ exchange mediated by Slc26a6 and Slc26a3 (1,9,17,26,29,31,59). Furthermore, in some conditions, the activity of CFTR alone may account for 50% or more of stimulated HCO 3 Ϫ secretion (20).…”

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confidence: 99%

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SLC26 anion exchangers of guinea pig pancreatic duct: molecular cloning and functional characterization

Stewart

Shmukler

Vandorpe

et al. 2011

American Journal of Physiology-Cell Physiology

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The secretin-stimulated human pancreatic duct secretes HCO3−-rich fluid essential for normal digestion. Optimal stimulation of pancreatic HCO3− secretion likely requires coupled activities of the cystic fibrosis transmembrane regulator (CFTR) anion channel and apical SLC26 Cl−/HCO3− exchangers. However, whereas stimulated human and guinea pig pancreatic ducts secrete ∼140 mM HCO3− or more, mouse and rat ducts secrete ∼40–70 mM HCO3−. Moreover, the axial distribution and physiological roles of SLC26 anion exchangers in pancreatic duct secretory processes remain controversial and may vary among mammalian species. Thus the property of high HCO3− secretion shared by human and guinea pig pancreatic ducts prompted us to clone from guinea pig pancreatic duct cDNAs encoding Slc26a3, Slc26a6, and Slc26a11 polypeptides. We then functionally characterized these anion transporters in Xenopus oocytes and human embryonic kidney (HEK) 293 cells. In Xenopus oocytes, gpSlc26a3 mediated only Cl−/Cl− exchange and electroneutral Cl−/HCO3− exchange. gpSlc26a6 in Xenopus oocytes mediated Cl−/Cl− exchange and bidirectional exchange of Cl− for oxalate and sulfate, but Cl−/HCO3− exchange was detected only in HEK 293 cells. gpSlc26a11 in Xenopus oocytes exhibited pH-dependent Cl−, oxalate, and sulfate transport but no detectable Cl−/HCO3− exchange. The three gpSlc26 anion transporters exhibited distinct pharmacological profiles of 36Cl− influx, including partial sensitivity to CFTR inhibitors Inh-172 and GlyH101, but only Slc26a11 was inhibited by PPQ-102. This first molecular and functional assessment of recombinant SLC26 anion transporters from guinea pig pancreatic duct enhances our understanding of pancreatic HCO3− secretion in species that share a high HCO3− secretory output.

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Section: C297mentioning

confidence: 42%

Section: Molecular Cloning Of Slc26a3 Slc26a6 and Slc26a11 Cdnas Frmentioning

confidence: 99%

mentioning

confidence: 99%

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SLC26 anion exchangers of guinea pig pancreatic duct: molecular cloning and functional characterization

Stewart

Shmukler

Vandorpe

et al. 2011

American Journal of Physiology-Cell Physiology

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“…It is generally accepted that SLC26A6 is electrogenic (Jiang et al, 2002;Ko et al, 2002;Xie et al, 2002) with an apparent stoichiometry of 1Cl -:2HCO 3 - (Shcheynikov et al, 2006), and early evidence suggested that SLC26A3 was also electrogenic, but with a stoichiometry of 2Cl -:1HCO 3 -, opposite that of SLC26A6 (Ko et al, 2002;Shcheynikov et al, 2006). However, more recent evidence indicates that SLC26A3 is electroneutral Lamprecht et al, 2005;Melvin et al, 1999). Both SLC26A3 and SLC26A6 are expressed in the possum intestine ), but the very low basal I sc in the possum duodenum suggests that if basal HCO 3 -secretion does occur, the overall process is electroneutral.…”

Section: Discussionmentioning

confidence: 98%

The distribution and expression of CFTR restricts electrogenic anion secretion to the ileum of the brushtail possum, Trichosurus vulpecula

Gill

Bartolo

Demmers

et al. 2011

Journal of Experimental Biology

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SUMMARYIn eutherian mammals, fluid secretion is essential for intestinal function. This is driven by electrogenic Cl -secretion, which involves a NaK2Cl cotransporter (NKCC1) in the enterocyte basolateral membrane and the cystic fibrosis transmembrane conductance regulator (CFTR) in the apical membrane. However, in the possum ileum, NKCC1 expression is low and secretagogues stimulate electrogenic HCO 3 -secretion driven by a basolateral NaHCO 3 cotransporter (pNBCe1). Here we investigated whether electrogenic anion secretion occurs in possum duodenum and jejunum and determined the role of CFTR in possum intestinal anion secretion. Prostaglandin E 2 (PGE 2 ) and forskolin stimulated a large increase in ileal short-circuit current (I sc ), consistent with electrogenic HCO 3 -secretion, but had little effect on the duodenal and jejunal I sc . Furthermore, 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB) and N-(2-naphthalenyl)-[(3,5-dibromo-2,4-dihydroxyphenyl)methylene]glycine hydrazide (GlyH101) inhibited cloned possum CFTR in cultured cells and the PGE 2 -stimulated ileal I sc , implicating CFTR in ileal HCO 3 -secretion. Consistent with this, CFTR is expressed in the apical membrane of ileal crypt and lower villous cells, which also express pNBCe1 in the basolateral membrane. In contrast, duodenal and jejunal CFTR expression is low relative to the ileum. Jejunal pNBCe1 expression is also low, whereas duodenal and ileal pNBCe1 expression are comparable. All regions have low NKCC1 expression. These results indicate that cAMP-dependent electrogenic Cl -secretion does not occur in the possum small intestine because of the absence of CFTR and NKCC1. Furthermore, CFTR functions as the apical anion conductance associated with HCO 3 -secretion and its distribution limits electrogenic HCO 3 -secretion to the ileum.

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“…SAT, which can exchange sulfate for CO 3 2-, is present at the basolateral membranes of small intestine and renal proximal tubule. Another SAT-family member, DRA (down-regulated in adenoma) encodes a Cl-HCO 3 exchanger present in apical membranes of certain small-intestine cells [38] and pancreatic ducts [39]. Along with cystic fibrosis transmembrane conductance regulator (CFTR) and NBCe1-B, DRA may play a critical role in the secretion of HCO 3 -by the pancreatic duct.…”

Section: Other Hco 3 -Transportersmentioning

confidence: 99%

Sodium-Coupled Bicarbonate Transporters

Boron

2008

Seldin and Giebisch's the Kidney

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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

Cited by 251 publications

References 45 publications

SLC26 anion exchangers of guinea pig pancreatic duct: molecular cloning and functional characterization

SLC26 anion exchangers of guinea pig pancreatic duct: molecular cloning and functional characterization

The distribution and expression of CFTR restricts electrogenic anion secretion to the ileum of the brushtail possum, Trichosurus vulpecula

Sodium-Coupled Bicarbonate Transporters

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