Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0001430 (adenoma)
 21,222 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

HCO3(-) secretion is the most important defense mechanism against acid injury in the duodenum. However, the identity of the transporter(s) mediating apical HCO3(-) secretion in the duodenum remains unknown. A family of anion exchangers, which include downregulated in adenoma (DRA or SLC26A3), pendrin (PDS or SLC26A4), and the putative anion transporter (PAT1 or SLC26A6) has recently been identified. DRA and pendrin mediate Cl(-)/base exchange; however, the functional identity and distribution of PAT1 (SLC26A6) is not known. In these studies, we investigated the functional identity, tissue distribution, and membrane localization of PAT1. Expression studies in Xenopus oocytes demonstrated that PAT1 functions in Cl(-)/HCO3(-) exchange mode. Tissue distribution studies indicated that the expression of PAT1 is highly abundant in the small intestine but is low in the colon, a pattern opposite that of DRA. PAT1 was also abundantly detected in stomach and heart. Immunoblot analysis studies identified PAT1 as a approximately 90 kDa protein in the duodenum. Immunohistochemical studies localized PAT1 to the brush border membranes of the villus cells of the duodenum. We propose that PAT1 is an apical Cl(-)/HCO3(-) exchanger in the small intestine.
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PMID:Identification of an apical Cl(-)/HCO3(-) exchanger in the small intestine. 1184 9

Normal human colonic luminal (NH(4)(+)) concentration ([NH(4)(+)]) ranges from approximately 10 to 100 mM. However, the nature of the effects of NH(4)(+) on transport, as well as NH(4)(+) transport itself, in colonic epithelium is poorly understood. We elucidate here the effects of apical NH(4)(+) on cAMP-stimulated Cl(-) secretion in colonic T84 cells. In HEPES-buffered solutions, 10 mM apical NH(4)(+) had no significant effect on cAMP-stimulated current. In contrast, 10 mM apical NH(4)(+) reduced current within 5 min to 61 +/- 4% in the presence of 25 mM HCO(3)(-). Current inhibition was not simply due to an increase in extracellular K(+)-like cations, in that the current magnitude was 95 +/- 5% with 10 mM apical K(+) and 46 +/- 3% with 10 mM apical NH(4)(+) relative to that with 5 mM apical K(+). We previously demonstrated that inhibition of Cl(-) secretion by basolateral NH(4)(+) occurs in HCO(3)(-)-free conditions and exhibits anomalous mole fraction behavior. In contrast, apical NH(4)(+) inhibition of current in HCO(3)(-) buffer did not show anomalous mole fraction behavior and followed the absolute [NH(4)(+)] in K(+)-NH(4)(+) mixtures, where K(+) concentration + [NH(4)(+)] = 10 mM. The apical NH(4)(+) inhibitory effect was not prevented by 100 microM methazolamide, suggesting no role for apical carbonic anhydrase. However, apical NH(4)(+) inhibition of current was prevented by 10 min of pretreatment of the apical surface with 500 microM DIDS, 100 microM 4,4'-dinitrostilbene-2,2'-disulfonic acid (DNDS), or 25 microM niflumic acid, suggesting a role for NH(4)(+) action through an apical anion exchanger. mRNA and protein for the apical anion exchangers SLC26A3 [downregulated in adenoma (DRA)] and SLC26A6 [putative anion transporter (PAT1)] were detected in T84 cells by RT-PCR and Northern and Western blots. DRA and PAT1 appear to associate with CFTR in the apical membrane. We conclude that the HCO(3)(-) dependence of apical NH(4)(+) inhibition of secretion is due to the action of NH(4)(+) on an apical anion exchanger.
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PMID:Apical ammonium inhibition of cAMP-stimulated secretion in T84 cells is bicarbonate dependent. 1600 64

Lysophosphatidic acid (LPA), a potent bioactive phospholipid, is a natural component of food products like soy and egg yolk. LPA modulates a number of epithelial functions and has been shown to inhibit cholera toxin-induced diarrhea. Antidiarrheal effects of LPA are known to be mediated by inhibiting chloride secretion. However, the effects of LPA on chloride absorption in the mammalian intestine are not known. The present studies examined the effects of LPA on apical Cl(-)/OH(-) exchangers known to be involved in chloride absorption in intestinal epithelial cells. Caco-2 cells were treated with LPA, and Cl(-)/OH(-) exchange activity was measured as DIDS-sensitive (36)Cl(-) uptake. Cell surface biotinylation studies were performed to evaluate the effect of LPA on cell surface levels of apical Cl(-)/OH(-) exchangers, downregulated in adenoma (DRA) (SLC26A3), and putative anion transporter-1 (SLC26A6). Treatment of Caco-2 cells with LPA (100 muM) significantly stimulated Cl(-)/OH(-) exchange activity. Specific agonist for LPA2 receptor mimicked the effects of LPA. LPA-mediated stimulation of Cl(-)/OH(-) exchange activity was dependent on activation of phosphatidylinositol 3-kinase/Akt signaling pathway. Consistent with the functional activity, LPA treatment resulted in increased levels of DRA on the apical membrane. Our results demonstrate that LPA stimulates apical Cl(-)/OH(-) exchange activity and surface levels of DRA in intestinal epithelial cells. This increase in Cl(-)/OH(-) exchange may contribute to the antidiarrheal effects of LPA.
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PMID:Mechanisms of lysophosphatidic acid (LPA) mediated stimulation of intestinal apical Cl-/OH- exchange. 1991 May 24

Two members of the SLC26 gene family, SLC26A3 or DRA (downregulated in adenoma) and SLC26A6 (putative anion transporter 1, PAT1), are known to play a major role in apical Cl(-)/OH(-) (HCO(3)(-)) exchange process in the human intestine. We have previously shown the inhibitory effects of IFN-gamma (30 ng/ml, 24 h) on both SLC26A3 and A6 expression and promoter activity. We also demonstrated that the effects of IFN-gamma on SLC26A6 gene expression were mediated via IRF-1 transcription factor. However, the molecular mechanisms underlying the transcriptional modulation of SLC26A3 gene expression by IFN-gamma in the intestine are not known. The present studies were, therefore, designed to elucidate the signaling mechanisms and transcription factor(s) involved in mediating the inhibitory effects of IFN-gamma on DRA promoter (p--1183/+114) activity. Deletion analysis indicated that the IFN-gamma response element is located within the -1183 to -790 region, and sequence analysis of this region revealed the presence of potential gamma-activated site (GAS), a binding site (-933/-925 bp) for signal transducer and activator of transcription factor 1 (STAT1). Mutations in the potential GAS element abrogated the inhibitory effects of IFN-gamma. These studies provide evidence for the involvement of STAT1 in the inhibition of SLC26A3 gene expression by IFN-gamma in the human intestine.
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PMID:Mechanisms of transcriptional modulation of the human anion exchanger SLC26A3 gene expression by IFN-{gamma}. 1994 27

The worldwide increase in the incidence of metabolic syndrome correlates with marked increase in total fructose intake in the form of high-fructose corn syrup, beverage and table sugar. Increased dietary fructose intake in rodents has been shown to recapitulate many aspects of metabolic syndrome by causing hypertension, insulin resistance and hyperlipidaemia. Recent studies demonstrated that increased dietary fructose intake stimulates salt absorption in the small intestine and kidney tubules, resulting in a state of salt overload and thus causing hypertension. The absorption of salt (sodium and chloride) in the small intestine is predominantly mediated via the chloride/base exchangers DRA (Down Regulated in Adenoma) (SLC26A3) and PAT1 (Putative Anion Transporter 1) (SLC26A6), and the Na(+) /H(+) exchanger NHE3 (Sodium Hydrogen Exchanger3) (SLC9A3). PAT1 and NHE3 also co-localize on the apical membrane of kidney proximal tubule. Luminal fructose stimulated salt absorption in the jejunum and kidney tubules, responses that were significantly diminished in PAT1 null mice. These studies further demonstrated that Glut5 (SLC2A5) is the major fructose-absorbing transporter in the small intestine (and kidney proximal tubule) and plays an essential role in the systemic homeostasis of fructose. Increased dietary fructose intake for several weeks upregulated the expression of NHE3, PAT1 and Glut5 in the intestine and resulted in hypertension in wild-type mice, a response that was almost abolished in PAT1 null mice and abrogated in Glut5 null mice. This article will discuss the interaction of Glut5 with salt-absorbing transporters and review the role of dietary fructose in enhanced salt absorption in intestine and kidney as it relates to the pathogenesis of hypertension in metabolic syndrome.
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PMID:Dietary fructose, salt absorption and hypertension in metabolic syndrome: towards a new paradigm. 2114 27