Publications

• The Pendred syndrome gene encodes a chloride-iodide transport protein.

  Scott D.A., Wang R., Kreman T.M., Sheffield V.C., Karnishki L.P.

  Pendred syndrome is the most common form of syndromic deafness and characterized by congenital sensorineural hearing loss and goitre. This disorder was mapped to chromosome 7 and the gene causing Pendred syndrome (PDS) was subsequently identified by positional cloning. PDS encodes a putative trans ... >> More

  Pendred syndrome is the most common form of syndromic deafness and characterized by congenital sensorineural hearing loss and goitre. This disorder was mapped to chromosome 7 and the gene causing Pendred syndrome (PDS) was subsequently identified by positional cloning. PDS encodes a putative transmembrane protein designated pendrin. Pendrin is closely related to a family of sulfate transport proteins that includes the rat sulfate-anion transporter (encoded by Sat-1; 29% amino acid sequence identity), the human diastrophic dysplasia sulfate transporter (encoded by DTD; 32%) and the human sulfate transporter 'downregulated in adenoma' (encoded by DRA; 45%). On the basis of this homology and the presence of a slightly modified sulfate-transporter signature sequence comprising its putative second transmembrane domain, pendrin has been proposed to function as a sulfate transporter. We were unable to detect evidence of sulfate transport following the expression of pendrin in Xenopus laevis oocytes by microinjection of PDS cRNA or in Sf9 cells following infection with PDS-recombinant baculovirus. The rates of transport for iodide and chloride were significantly increased following the expression of pendrin in both cell systems. Our results demonstrate that pendrin functions as a transporter of chloride and iodide, but not sulfate, and may provide insight into thyroid physiology and the pathophysiology of Pendred syndrome. << Less

  Nat. Genet. 21:440-443(1999) [PubMed] [EuropePMC]

• The Slc26a4 transporter functions as an electroneutral Cl-/I-/HCO3- exchanger: role of Slc26a4 and Slc26a6 in I- and HCO3- secretion and in regulation of CFTR in the parotid duct.

  Shcheynikov N., Yang D., Wang Y., Zeng W., Karniski L.P., So I., Wall S.M., Muallem S.

  Transcellular Cl(-) and HCO(3)(-) transport is a vital function of secretory epithelia and exit across the luminal membrane is mediated by members of the SLC26 transporters in conjunction with cystic fibrosis transmembrane conductance regulator (CFTR) channel. Typically, secretory epithelia expres ... >> More

  Transcellular Cl(-) and HCO(3)(-) transport is a vital function of secretory epithelia and exit across the luminal membrane is mediated by members of the SLC26 transporters in conjunction with cystic fibrosis transmembrane conductance regulator (CFTR) channel. Typically, secretory epithelia express several SLC26 transporters in the same tissue; however, how their specific function is determined in vivo is not known. In the present work we used the parotid gland duct which expressed Slc26a4 and Slc26a6 and the model systems of Slc26a4(-/-) and Slc26a6(-/-) mice to study the role and regulation of these SLC26 transporters. We examined the transport modes of SLC26A4 expressed in Xenopus oocytes and report that SLC26A4 functions as a coupled, electroneutral I(-)/Cl(-), I(-)/HCO(3)(-) and Cl(-)/HCO(3)(-) exchanger with 1: 1 stoichiometry, with I(-) as the preferred anion. In the duct, Slc26a4 is expressed in the luminal membrane and mainly mediates I(-) secretion with minimal role in luminal HCO(3)(-) transport. By contrast, Slc26a6 mediates luminal Cl(-)/HCO(3)(-) exchange activity with minimal role in I(-) secretion. Furthermore, silencing of CFTR altered Cl(-)/HCO(3)(-) exchange by Slc26a6, but had no effect on I(-) secretion by Slc26a4. Accordingly, deletion of Slc26a6, but not deletion of Slc26a4, results in dysregulation of CFTR. These findings provide the first evidence for a selective role of the SLC26 transporters expressed in the same tissue in epithelial anion transport and suggest that transport specificity is achieved by both the properties of the transporters and the composition of the complexes they form. << Less

  J. Physiol. (Lond.) 586:3813-3824(2008) [PubMed] [EuropePMC]

  This publication is cited by 2 other entries.

• Solute carrier family 26 member a2 (Slc26a2) protein functions as an electroneutral SOFormula/OH-/Cl- exchanger regulated by extracellular Cl-.

  Ohana E., Shcheynikov N., Park M., Muallem S.

  Slc26a2 is a ubiquitously expressed SO(4)(2-) transporter with high expression levels in cartilage and several epithelia. Mutations in SLC26A2 are associated with diastrophic dysplasia. The mechanism by which Slc26a2 transports SO(4)(2-) and the ion gradients that mediate SO(4)(2-) uptake are poor ... >> More

  Slc26a2 is a ubiquitously expressed SO(4)(2-) transporter with high expression levels in cartilage and several epithelia. Mutations in SLC26A2 are associated with diastrophic dysplasia. The mechanism by which Slc26a2 transports SO(4)(2-) and the ion gradients that mediate SO(4)(2-) uptake are poorly understood. We report here that Slc26a2 functions as an SO(4)(2-)/2OH(-), SO(4)(2-)/2Cl(-), and SO(4)(2-)/OH(-)/Cl(-) exchanger, depending on the Cl(-) and OH(-) gradients. At inward Cl(-) and outward pH gradients (high Cl(-)(o) and low pH(o)) Slc26a2 functions primarily as an SO(4)(2-)(o)/2OH(-)(i) exchanger. At low Cl(-)(o) and high pH(o) Slc26a2 functions increasingly as an SO(4)(2-)(o)/2Cl(-)(i) exchanger. The reverse is observed for SO(4)(2-)(i)/2OH(-)(o) and SO(4)(2-)(i)/2Cl(-)(o) exchange. Slc26a2 also exchanges Cl(-) for I(-), Br(-), and NO(3)(-) and Cl(-)(o) competes with SO(4)(2-) on the transport site. Interestingly, Slc26a2 is regulated by an extracellular anion site, required to activate SO(4)(2-)(i)/2OH(-)(o) exchange. Slc26a2 can transport oxalate in exchange for OH(-) and/or Cl(-) with properties similar to SO(4)(2-) transport. Modeling of the Slc26a2 transmembrane domain (TMD) structure identified a conserved extracellular sequence (367)GFXXP(371) between TMD7 and TMD8 close to the conserved Glu(417) in the permeation pathway. Mutation of Glu(417) eliminated transport by Slc26a2, whereas mutation of Phe(368) increased the affinity for SO(4)(2-)(o) 8-fold while reducing the affinity for Cl(-)(o) 2 fold, but without affecting regulation by Cl(-)(o). These findings clarify the mechanism of net SO(4)(2-) transport and describe a novel regulation of Slc26a2 by an extracellular anion binding site and should help in further understanding aberrant SLC26A2 function in diastrophic dysplasia. << Less

  J. Biol. Chem. 287:5122-5132(2012) [PubMed] [EuropePMC]

  This publication is cited by 4 other entries.