PAT-1 (Slc26a6) is the predominant apical membrane Cl−/HCO3− exchanger in the upper villous epithelium of the murine duodenum

Simpson, Janet E.; Schweinfest, Clifford W.; Shull, Gary E.; Gawenis, Lara R.; Walker, Nancy M.; Boyle, Kathryn T.; Soleimani, Manoocher; Clarke, Lane L.

doi:10.1152/ajpgi.00354.2006

Cited by 103 publications

(117 citation statements)

References 43 publications

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“…3D shows nonsignificant increases in Cl Ϫ /HCO 3 Ϫ exchange-associated outward current recorded at holding potentials of Ϫ30 and Ϫ90 mV for human SLC26A3 and gpSlc26a3. These data together suggest that gpSlc26a3, like human SLC26A3 (8,17,26) and mouse Slc26a3 (1,46), mediates electroneutral Cl Ϫ /HCO 3 Ϫ exchange, in contrast to reports of electrogenic Cl Ϫ /HCO 3 Ϫ exchange by mouse Slc26a3 (33,44).…”

Section: Molecular Cloning Of Slc26a3 Slc26a6 and Slc26a11 Cdnas Frmentioning

confidence: 71%

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: Molecular Cloning Of Slc26a3 Slc26a6 and Slc26a11 Cdnas Frmentioning

confidence: 71%

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 well known that multiple anion exchangers reside in the membranes of intestinal cells, and there has been little characterization of their ability to mediate the transport of Cu-anion complexes. However, the ability of the AE1 anion exchanger found in red blood cells to mediate such transport, as well as that of other related heavy metal ion complexes, is well documented (1,23,32,40,41).…”

Section: Discussionmentioning

confidence: 99%

Acquisition of dietary copper: a role for anion transporters in intestinal apical copper uptake

Zimnicka

Ivy

Kaplan

2011

American Journal of Physiology-Cell Physiology

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Copper is an essential micronutrient in humans and is required for a wide range of physiological processes, including neurotransmitter biosynthesis, oxidative metabolism, protection against reactive oxygen species, and angiogenesis. The first step in the acquisition of dietary copper is absorption from the intestinal lumen. The major human high-affinity copper uptake protein, human copper transporter hCTR1, was recently shown to be at the basolateral or blood side of both intestinal and renal epithelial cell lines and thus does not play a direct role in this initial step. We sought to functionally identify the major transport pathways available for the absorption of dietary copper across the apical intestinal membrane using Caco2 cells, a well-established model for human enterocytes. The initial rate of apical copper uptake into confluent monolayers of Caco2 cells is greatly elevated if amino acids and serum proteins are removed from the growth media. Uptake from buffered saline solutions at neutral pH (but not at lower pH) is inhibited by either d- or l-histidine, unaltered by the removal of sodium ions, and inhibited by ∼90% when chloride ions are replaced by gluconate or sulfate. Chloride-dependent copper uptake occurs with Cu(II) or Cu(I), although Cu(I) uptake is not inhibited by histidine, nor by silver ions. A well-characterized inhibitor of anion exchange systems, DIDS, inhibited apical copper uptake by 60–70%, while the addition of Mn(II) or Fe(II), competitive substrates for the divalent metal transporter DMT1, had no effect on copper uptake. We propose that anion exchangers play an unexpected role in copper absorption, utilizing copper-chloride complexes as pseudo-substrates. This pathway is also observed in mouse embryonic fibroblasts, human embryonic kidney cells, and Cos-7 cells. The special environment of low pH, low concentration of protein, and protonation of amino acids in the early intestinal lumen make this pathway especially important in dietary copper acquisition.

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“…It is notable that in the possum ileum, CFTR expression is limited to the crypts and the base of the villi, whereas pNBCe1 expression extends further towards the tip of the villi. In eutherian mammals, the SLC26 transporters associated with HCO 3 -secretion are expressed primarily in the villi (Simpson et al, 2007;Wang et al, 2002). Furthermore, HCO 3 -secretion through Cl --HCO 3 -exchange also occurs in the ileum and proximal colon of eutherian mammals (Knickelbein et al, 1985;Mugharbil et al, 1990;Rajendran and Binder, 1993) and is an important mechanism of HCO 3 -secretion in other vertebrates, particularly marine teleosts (Grosell, 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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PAT-1 (Slc26a6) is the predominant apical membrane Cl⁻/HCO₃⁻ exchanger in the upper villous epithelium of the murine duodenum

Abstract: Simpson JE, Schweinfest CW, Shull GE, Gawenis LR, Walker NM, Boyle KT, Soleimani M, Clarke LL. PAT-1 (Slc26a6) is the predominant apical membrane Cl Ϫ /HCO 3 Ϫ exchanger in the upper villous epithelium of the murine duodenum.

Cited by 103 publications

References 43 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

Acquisition of dietary copper: a role for anion transporters in intestinal apical copper uptake

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

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