Role of Down-Regulated in Adenoma Anion Exchanger in HCO3– Secretion Across Murine Duodenum

Walker, Nancy M.; Simpson, Janet E.; Brazill, Jennifer M.; Gill, Ravinder K.; Dudeja, Pradeep K.; Schweinfest, Clifford W.; Clarke, Lane L.

doi:10.1053/j.gastro.2008.11.016

Cited by 70 publications

(87 citation statements)

References 40 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%

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%

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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Section: Discussionmentioning

confidence: 99%

“…However, an important function of HCO 3 -secretion in the duodenum is protection of the duodenal epithelium from the acidic chyme delivered from the stomach into the small intestine (Allen and Flemstrom, 2005 of the eutherian duodenum are SLC26A3 and SLC26A6 (Jacob et al, 2002;Singh et al, 2008;Tuo et al, 2006;Walker et al, 2009). However, SLC26A6 contributes little to HCO 3 -secretion (Wang et al, 2005) whereas SLC26A3 is responsible for ~60% of the spontaneous HCO 3 -secretion and ~50% of the cAMP-stimulated secretion, CFTR and a small paracellular leak accounting for the remainder (Walker et al, 2009). 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).…”

Section: Discussionmentioning

confidence: 99%

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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“…In mice, a similarly patchy DRA immunolabeling pattern was described in duodenal villi (54), and modest DRA labeling was reported in jejunum villi relative to the surface epithelium of the cecum (56), using a different antibody. In our CFTR/DRA double-labeling experiments, DRA was not detected in CHE cells (data not shown).…”

Section: G459 Cftr High Expresser Cellsmentioning

confidence: 99%

Characterization of CFTR High Expresser cells in the intestine

Jakab¹,

Collaco²,

Ameen

2013

American Journal of Physiology-Gastrointestinal and Liver Physi

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The CFTR High Expresser (CHE) cells express eightfold higher levels of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl− channel compared with neighboring enterocytes and were first identified by our laboratory (Ameen et al., Gastroenterology 108: 1016, 1995). We used double-label immunofluorescence microscopy to further study these enigmatic epithelial cells in rat intestine in vivo or ex vivo. CHE cells were found in duodenum, most frequent in proximal jejunum, and absent in ileum and colon. CFTR abundance increased in CHE cells along the crypt-villus axis. The basolateral Na+K+Cl− cotransporter NKCC1, a key transporter involved in Cl− secretion, was detected at similar levels in CHE cells and neighboring enterocytes at steady state. Microvilli appeared shorter in CHE cells, with low levels of Myosin 1a, a villus enterocyte-specific motor that retains sucrase/isomaltase in the brush-border membrane (BBM). CHE cells lacked alkaline phosphatase and absorptive villus enterocyte BBM proteins, including Na+H+ exchanger NHE3, Cl−/HCO3− exchanger SLC26A6 (putative anion exchanger 1), and sucrase/isomaltase. High levels of the vacuolar-ATPase proton pump were observed in the apical domain of CHE cells. Levels of the NHE regulatory factor NHERF1, Na-K-ATPase, and Syntaxin 3 were similar to that of neighboring enterocytes. cAMP or acetylcholine stimulation robustly increased apical CFTR and basolateral NKCC1 disproportionately in CHE cells relative to neighboring enterocytes. These data strongly argue for a specialized role of CHE cells in Cl−-mediated “high-volume” fluid secretion on the villi of the proximal small intestine.

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Role of Down-Regulated in Adenoma Anion Exchanger in HCO3– Secretion Across Murine Duodenum

Cited by 70 publications

References 40 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

Characterization of CFTR High Expresser cells in the intestine

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