Characterization of SLC26A9, Facilitation of Cl&lt;sup&gt;-&lt;/sup&gt; Transport by Bicarbonate

Loriol, Céline; Dulong, Sandrine; Avella, Martine; Gabillat, Nicole; Boulukos, Kim E.; Borgèse, Franck; Ehrenfeld, Jordi

doi:10.1159/000149780

Cited by 70 publications

(93 citation statements)

References 45 publications

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“…The CFTR inh -172- insensitive I sc was completely inhibited by bumetanide in tissues from both wild-type and Slc26a9 -/-mice ( Figure 1H). To determine, whether SLC26A9-mediated Cl -transport and functional interaction with CFTR required the presence of HCO 3 - (10,11,14), we compared bioelectric properties in wild-type and Slc26a9 -/-bronchi in the absence and presence of HCO 3 -. HCO 3 -had no effect on basal I sc , constitutive Cl -secretion (amiloride-insensitive I sc ), or cAMP-induced Cl -secretion, and, as in HCO 3 --free conditions, constitutive and cAMP-dependent Cl -secretion were not different in wild-type compared with Slc26a9 -/-tissues (Supplemental Figure 2).…”

Section: Resultsmentioning

confidence: 99%

“…SLC26A9 (solute carrier family 26, member 9) is a member of the SLC26 family of anion transporters predominantly expressed in epithelia of the lung and upper GI tract (8,9). Recent studies showed that the SLC26A9 protein functions as a Cl -channel with minimal HCO 3 -conductance that is regulated by CFTR and WNK kinases in heterologous cells (10)(11)(12)(13). Further, SLC26A9 contributes to constitutive and cAMP-dependent Cl -secretion in human bronchial epithelial (HBE) cells, where it has been suggested to interact functionally with CFTR in vitro (11,14).…”

Section: Introductionmentioning

confidence: 99%

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SLC26A9-mediated chloride secretion prevents mucus obstruction in airway inflammation

Anagnostopoulou¹,

Riederer²,

Duerr³

et al. 2012

J. Clin. Invest.

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Asthma is a chronic condition with unknown pathogenesis, and recent evidence suggests that enhanced airway epithelial chloride (Cl -) secretion plays a role in the disease. However, the molecular mechanism underlying Cl -secretion and its relevance in asthma pathophysiology remain unknown. To determine the role of the solute carrier family 26, member 9 (SLC26A9) Cl -channel in asthma, we induced Th2-mediated inflammation via IL-13 treatment in wild-type and Slc26a9-deficient mice and compared the effects on airway ion transport, morphology, and mucus content. We found that IL-13 treatment increased Cl -secretion in the airways of wildtype but not Slc26a9-deficient mice. While IL-13-induced mucus overproduction was similar in both strains, treated Slc26a9-deficient mice exhibited airway mucus obstruction, which did not occur in wild-type controls. In a study involving healthy children and asthmatics, a polymorphism in the 3′ UTR of SLC26A9 that reduced protein expression in vitro was associated with asthma. Our data demonstrate that the SLC26A9 Cl -channel is activated in airway inflammation and suggest that SLC26A9-mediated Cl -secretion is essential for preventing airway obstruction in allergic airway disease. These results indicate that SLC26A9 may serve as a therapeutic target for airway diseases associated with mucus plugging.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

SLC26A9-mediated chloride secretion prevents mucus obstruction in airway inflammation

Anagnostopoulou¹,

Riederer²,

Duerr³

et al. 2012

J. Clin. Invest.

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“…Slc26a9 has been reported to be a Cl Ϫ -HCO 3 Ϫ exchanger (9, 10) or a large Cl Ϫ conductance (3,11,12). Loriol and co-workers (12) indicated that SLC26A9 has a Cl Ϫ conductance that may be stimulated by HCO 3 Ϫ .…”

Section: Slc26 Proteins Function As Anion Exchangers Channels and Smentioning

confidence: 99%

“…These investigators hypothesized that this stimulatory interaction could account for the differences in pancreatic insufficiency and sufficiency observed in cystic fibrosis patients. Nevertheless, knock-out Slc26a6 mouse studies reveal more complicated cell and tissue physiology (see "Discussion").Slc26a9 has been reported to be a Cl Ϫ -HCO 3 Ϫ exchanger (9, 10) or a large Cl Ϫ conductance (3,11,12). Loriol and co-workers (12) indicated that SLC26A9 has a Cl Ϫ conductance that may be stimulated by HCO 3 Ϫ .…”

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confidence: 99%

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Slc26a9 Is Inhibited by the R-region of the Cystic Fibrosis Transmembrane Conductance Regulator via the STAS Domain

Chang

Plata

Sinđić

et al. 2009

Journal of Biological Chemistry

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SLC26 proteins function as anion exchangers, channels, and sensors. Previous cellular studies have shown that Slc26a3 and Slc26a6 interact with the R-region of the cystic fibrosis transmembrane conductance regulator (CFTR), (R)CFTR, via theSlc26 genes and proteins have attracted the attention of physiologists and geneticists. Why? Slc26a1 (Sat-1) was characterized as a Na ϩ -independent SO 4 2Ϫ transporter (1). Given the transport characteristics of the founding member of the gene family, Slc26 proteins were assumed to be sulfate transporters. Disease phenotypes, clone characterization, and family additions demonstrate that the Slc26 proteins are anion transporters or channels (2-4). These proteins have varied tissue expression patterns. At one extreme, Slc26a5 in mammals is found in the hair cells of the inner ear (5), whereas Slc26a2 (DTDST) is virtually ubiquitous in epithelial tissues (2).Several Slc26 proteins are found in the epithelia of the lung, intestine, stomach, pancreas, and kidney, usually in apical membranes. Interestingly these are also tissues and membranes in which the cystic fibrosis transmembrane conductance regulator (CFTR) 5 has been found functionally or by immunohistochemistry. Ko and co-workers (6 -8) examined the distribution of Slc26a3 and Slc26a6 in HCO 3 Ϫ secretory epithelia, and asked if an interaction might occur between these Slc26 proteins and CFTR. In particular, these studies indicate that in expression systems, there is a reciprocal-stimulatory interaction of the STAS (sulfate transporter anti-sigma) domains of Slc26a3 and Slc26a6 with the regulatory region (R-region) of CFTR. These investigators hypothesized that this stimulatory interaction could account for the differences in pancreatic insufficiency and sufficiency observed in cystic fibrosis patients. Nevertheless, knock-out Slc26a6 mouse studies reveal more complicated cell and tissue physiology (see "Discussion").Slc26a9 has been reported to be a Cl Ϫ -HCO 3 Ϫ exchanger (9, 10) or a large Cl Ϫ conductance (3,11,12). Loriol and co-workers (12) indicated that SLC26A9 has a Cl Ϫ conductance that may be stimulated by HCO 3 Ϫ . Two other groups have indicated that the Cl Ϫ conductance is not affected by the presence of HCO 3 Ϫ (10, 11). We have recently demonstrated that Slc26a9 functions as both an electrogenic nCl Ϫ -HCO 3 Ϫ exchanger and a Cl Ϫ channel (10). Dorwart and colleagues (11) found that WNK kinases inhibited the SLC26A9 Cl Ϫ conductance but that this effect was independent of kinase activity. One group has a preliminary report indicating that WNK3 decreased Cl Ϫ uptake,

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Slc26 Family of Anion Transporters in the Gastrointestinal Tract: Expression, Function, Regulation, and Role in Disease

Seidler

Nikolovska

2019

Comprehensive Physiology

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SLC26 family members are multifunctional transporters of small anions, including Cl − , HCO 3 − , sulfate, oxalate, and formate. Most SLC26 isoforms act as secondary (coupled) anion transporters, while others mediate uncoupled electrogenic transport resembling Cl − channels. Of the 11 described SLC26 isoforms, the SLC26A1,2,3,6,7,9,11 are expressed in the gastrointestinal tract, where they participate in salt and water transport, surface pH‐microclimate regulation, affect the microbiome composition, the absorption, and secretion of oxalate and sulfate, and other functions that require further study. Several intestinal or extra‐intestinal diseases are related to SLC26A mutations. Patients with congenital chloride diarrhea (CLD) suffer from Cl − ‐rich acidic diarrhea and systemic alkalosis due to SLC26A3 mutations. Patients with osteochondrodysplastic syndromes experience skeletal defects due to SLC26A2 mutations, resulting in defective sulfate absorption in enterocytes and sulfate uptake in chondrocytes. Because of functional interactions between SLC26 and other proteins, such as the Cl − channel CFTR, some of the intestinal cystic fibrosis manifestations may be attributed to impaired SLC26 isoform localization and function. The altered expression of SLC26 members due to inflammation or operative procedures have important consequences on intestinal transport and barrier function in common diseases as inflammatory bowel disease or bariatric surgery. The present review gives an overview on the current state of knowledge of the intestinally expressed SLC26A isoforms (SLC26A1,2,3,6,7,9,11) from the history of their functional identification, cloning and expression, the insights into their function, interaction partners and regulation gained in heterologous expression systems and Slc26a‐deficient mice, to information about their transcriptional regulation and roles in gastrointestinal disease manifestations. © 2019 American Physiological Society. Compr Physiol 9:839‐872, 2019.

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Characterization of SLC26A9, Facilitation of Cl<sup>-</sup> Transport by Bicarbonate

Cited by 70 publications

References 45 publications

SLC26A9-mediated chloride secretion prevents mucus obstruction in airway inflammation

SLC26A9-mediated chloride secretion prevents mucus obstruction in airway inflammation

Slc26a9 Is Inhibited by the R-region of the Cystic Fibrosis Transmembrane Conductance Regulator via the STAS Domain

Slc26 Family of Anion Transporters in the Gastrointestinal Tract: Expression, Function, Regulation, and Role in Disease

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