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

Abstract

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,

Novel Role for Pendrin in Orchestrating Bicarbonate Secretion in Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)-expressing Airway Serous Cells

“…Co-expression studies in HEK cells showed that CFTR expression led to a marked increase in Cl Ϫ /OH Ϫ and Cl Ϫ /HCO 3 Ϫ exchange mediated by SLC26A3, -A4, and -A6 (48). It is also possible that, under resting conditions, association between CFTR and pendrin blocks AE activity, a phenomenon recently described for Slc26a9 and the regulatory domain of CFTR in Xenopus oocyte co-expression studies (49).…”

Prestin Surface Expression and Activity Are Augmented by Interaction with MAP1S, a Microtubule-associated Protein

“…Moreover, the STAS domain in SLC26A3 also interacts with cystic fibrosis transmembrane regulator, and this interaction reciprocally modulates cystic fibrosis transmembrane regulator channel function as well as SLC26A3 transporter function (35). In contrast, cystic fibrosis transmembrane regulator interacts with the STAS domain of SLC26A9 and inhibits Cl Ϫ currents as well as its Cl Ϫ -HCO 3 Ϫ exchange (36). Given these data, it was our expectation that MAP1S would modulate NLC.…”

SLC26A9-mediated chloride secretion prevents mucus obstruction in airway inflammation

“…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).…”