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Shmuel Muallem - One of the best experts on this subject based on the ideXlab platform.
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properties and function of the solute carrier 26 family of anion transporters
2016Co-Authors: Nikolay Shcheynikov, Ehud Ohana, Shmuel MuallemAbstract:The SLC26 family of anion transporters consists of 10 members that display remarkable functional and substrate diversity. Mutations in several members of the family have been identified as causing a variety of human diseases and mouse phenotype when deleted. The family drew the attention and strong interest of epithelial biologist with the identification of the first elusive luminal Cl−/HCO3− exchange, which turned to be the third member of the family SLC26A3. Fairly quick, progress since revealed that members of the family transport all halides, NO3−, SO42−, oxalate, and formate, among others. Members of the family can be grouped into three subgroups based on substrate selectivity and transport mode: the SO42− transporters SLC26A1 and SLC26A2; the anion exchangers 2Cl−/1HCO3− SLC26A3, 1Cl−/1HCO3− SLC26A4, and 1Cl−/2HCO3− SLC26A6; and the Cl− channels SLC26A7, SLC26A9, and SLC26A11. This chapter discusses structural features, transport properties, and regulation of the transporters that are essential to understand their functions and roles in human diseases.
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solute carrier family 26 member a2 slc26a2 protein functions as an electroneutral so42 oh cl exchanger regulated by extracellular cl
Journal of Biological Chemistry, 2012Co-Authors: Ehud Ohana, Nikolay Shcheynikov, Meeyoung Park, Shmuel MuallemAbstract:Slc26a2 is a ubiquitously expressed SO42− transporter with high expression levels in cartilage and several epithelia. Mutations in SLC26A2 are associated with diastrophic dysplasia. The mechanism by which Slc26a2 transports SO42− and the ion gradients that mediate SO42− uptake are poorly understood. We report here that Slc26a2 functions as an SO42−/2OH−, SO42−/2Cl−, and SO42−/OH−/Cl− exchanger, depending on the Cl− and OH− gradients. At inward Cl− and outward pH gradients (high Cl−o and low pHo) Slc26a2 functions primarily as an SO42−o/2OH−i exchanger. At low Cl−o and high pHo Slc26a2 functions increasingly as an SO42−o/2Cl−i exchanger. The reverse is observed for SO42−i/2OH−o and SO42−i/2Cl−o exchange. Slc26a2 also exchanges Cl− for I−, Br−, and NO3− and Cl−o competes with SO42− on the transport site. Interestingly, Slc26a2 is regulated by an extracellular anion site, required to activate SO42−i/2OH−o exchange. Slc26a2 can transport oxalate in exchange for OH− and/or Cl− with properties similar to SO42− transport. Modeling of the Slc26a2 transmembrane domain (TMD) structure identified a conserved extracellular sequence 367GFXXP371 between TMD7 and TMD8 close to the conserved Glu417 in the permeation pathway. Mutation of Glu417 eliminated transport by Slc26a2, whereas mutation of Phe368 increased the affinity for SO42−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 SO42− 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.
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diverse transport modes by the solute carrier 26 family of anion transporters
The Journal of Physiology, 2009Co-Authors: Ehud Ohana, Dongki Yang, Nikolay Shcheynikov, Shmuel MuallemAbstract:The solute carrier 26 (SLC26) transporters are anion transporters with diverse substrate specificity. Several members are ubiquitous while others show limited tissue distribution. They are expressed in many epithelia and to the extent known, play a central role in anion secretion and absorption. Members of the family are primarily Cl- transporters, although some members transport mainly SO(4)2-, Cl-, HCO(3)- or I-. A defining feature of the family is their functional diversity. Slc26a1 and Slc26a2 function as specific SO(4)2- transporters while Slc26a4 functions as an electroneutral Cl-/I-/HCO(3)- exchanger. SLC26A3 and Slc26a6 function as coupled electrogenic Cl-/HCO(3)- exchangers or as bona fide anion channels. SLC26A7 and SLC26A9 function exclusively as Cl- channels. This short review discusses the functional diversity of the SLC26 transporters.
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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
The Journal of Physiology, 2008Co-Authors: Nikolay Shcheynikov, Lawrence P. Karniski, Dongki Yang, Youxue Wang, Weizong Zeng, Insuk So, Susan M Wall, Shmuel MuallemAbstract:Transcellular Cl− and HCO3− 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−/HCO3− and Cl−/HCO3− 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 HCO3− transport. By contrast, Slc26a6 mediates luminal Cl−/HCO3− exchange activity with minimal role in I− secretion. Furthermore, silencing of CFTR altered Cl−/HCO3− 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.
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congenital chloride losing diarrhea causing mutations in the stas domain result in misfolding and mistrafficking of SLC26A3
Journal of Biological Chemistry, 2008Co-Authors: Michael R Dorwart, Nikolay Shcheynikov, Shmuel Muallem, Jennifer M R Baker, Julie D Formankay, Philip J ThomasAbstract:Congenital chloride-losing diarrhea (CLD) is a genetic disorder causing watery stool and dehydration. Mutations in SLC26A3 (solute carrier 26 family member 3), which functions as a coupled Cl(-)/HCO(3)(-) exchanger, cause CLD. SLC26A3 is a membrane protein predicted to contain 12 transmembrane-spanning alpha-helices and a C-terminal STAS (sulfate transporters and anti-sigma-factor) domain homologous to the bacterial anti-sigma-factor antagonists. The STAS domain is required for SLC26A3 Cl(-)/HCO(3)(-) exchange function and for the activation of cystic fibrosis transmembrane conductance regulator by SLC26A3. Here we investigate the molecular mechanism(s) by which four CLD-causing mutations (DeltaY526/7, I544N, I675/6ins, and G702Tins) in the STAS domain lead to disease. In a heterologous mammalian expression system biochemical, immunohistochemical, and ion transport experiments suggest that the four CLD mutations cause SLC26A3 transporter misfolding and/or mistrafficking. Expression studies with the isolated STAS domain suggest that the I675/6ins and G702Tins mutations disrupt the STAS domain directly, whereas limited proteolysis experiments suggest that the DeltaY526/7 and I544N mutations affect a later step in the folding and/or trafficking pathway. The data suggest that these CLD-causing mutations cause disease by at least two distinct molecular mechanisms, both ultimately leading to loss of functional protein at the plasma membrane.
Aminata Toure - One of the best experts on this subject based on the ideXlab platform.
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functional interaction of the cystic fibrosis transmembrane conductance regulator with members of the slc26 family of anion transporters slc26a8 and slc26a9 physiological and pathophysiological relevance
The International Journal of Biochemistry & Cell Biology, 2014Co-Authors: Elma El Khouri, Aminata ToureAbstract:The solute carrier 26 (SLC26) proteins are transmembrane proteins located at the plasma membrane of the cells and transporting a variety of monovalent and divalent anions, including chloride, bicarbonate, sulfate and oxalate. In humans, 11 members have been identified (SLC26A1 to SLC26A11) and although part of them display a very restricted tissue expression pattern, altogether they are widely expressed in the epithelial cells of the body where they contribute to the composition and the pH regulation of the secreted fluids. Importantly, mutations in SLC26A2, A3, A4, and A5 have been associated with distinct human genetic recessive disorders (i.e. diastrophic dysplasia, congenital chloride diarrhea, Pendred syndrome and deafness, respectively), demonstrating their essential and non-redundant functions in many tissues. During the last decade, physical and functional interactions of SLC26 members with the cystic fibrosis transmembrane conductance regulator (CFTR) have been highly documented, leading to the model of a crosstalk based on the binding of the SLC26 STAS domain to the CFTR regulatory domain. In this review, we will focus on the functional interaction of SLC26A8 and SLC26A9 with the CFTR channel. In particular we will highlight the newly published studies indicating that mutations in SLC26A8 and SLC26A9 proteins are associated with a deregulation of the CFTR anion transport activity in the pathophysiological context of the sperm and the pulmonary cells. These studies confirm the physiological relevance of SLC26 and CFTR cross-regulation, opening new gates for the treatment of cystic fibrosis.
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functional interaction of the cystic fibrosis transmembrane conductance regulator with members of the slc26 family of anion transporters slc26a8 and slc26a9 physiological and pathophysiological relevance
The International Journal of Biochemistry & Cell Biology, 2014Co-Authors: Elma El Khouri, Aminata ToureAbstract:Abstract The solute carrier 26 (SLC26) proteins are transmembrane proteins located at the plasma membrane of the cells and transporting a variety of monovalent and divalent anions, including chloride, bicarbonate, sulfate and oxalate. In humans, 11 members have been identified (SLC26A1 to SLC26A11) and although part of them display a very restricted tissue expression pattern, altogether they are widely expressed in the epithelial cells of the body where they contribute to the composition and the pH regulation of the secreted fluids. Importantly, mutations in SLC26A2 , A3 , A4 , and A5 have been associated with distinct human genetic recessive disorders ( i.e. diastrophic dysplasia, congenital chloride diarrhea, Pendred syndrome and deafness, respectively), demonstrating their essential and non-redundant functions in many tissues. During the last decade, physical and functional interactions of SLC26 members with the cystic fibrosis transmembrane conductance regulator (CFTR) have been highly documented, leading to the model of a crosstalk based on the binding of the SLC26 STAS domain to the CFTR regulatory domain. In this review, we will focus on the functional interaction of SLC26A8 and SLC26A9 with the CFTR channel. In particular we will highlight the newly published studies indicating that mutations in SLC26A8 and SLC26A9 proteins are associated with a deregulation of the CFTR anion transport activity in the pathophysiological context of the sperm and the pulmonary cells. These studies confirm the physiological relevance of SLC26 and CFTR cross-regulation, opening new gates for the treatment of cystic fibrosis. This article is part of a Directed Issue entitled: Cystic Fibrosis: From o-mics to cell biology, physiology, and therapeutic advances.
Elma El Khouri - One of the best experts on this subject based on the ideXlab platform.
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SLC26A3 deficiency is associated with epididymis dysplasia and impaired sperm fertilization potential in the mouse
Molecular Reproduction and Development, 2018Co-Authors: Brigitte Riederer, Elma El Khouri, Marjorie Whitfield, Laurence Stouvenel, Archana Kini, Patrick LoresAbstract:Members of the solute carrier 26 (SLC26) family have emerged as important players in mediating anions fluxes across the plasma membrane of epithelial cells, in cooperation with the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. Among them, SLC26A3 acts as a chloride/bicarbonate exchanger, highly expressed in the gastrointestinal, pancreatic and renal tissues. In humans, mutations in the SLC26A3 gene were shown to induce congenital chloride-losing diarrhea (CLD), a rare autosomal recessive disorder characterized by life-long secretory diarrhea. In view of some reports indicating subfertility in some male CLD patients together with SLC26-A3 and -A6 expression in the male genital tract and sperm cells, we analyzed the male reproductive parameters and functions of SLC26A3 deficient mice, which were previously reported to display CLD gastro-intestinal features. We show that in contrast to Slc26a6, deletion of SLC26A3 is associated with severe lesions and abnormal cytoarchitecture of the epididymis, together with sperm quantitative, morphological and functional defects, which altogether compromised male fertility. Overall, our work provides new insight into the pathophysiological mechanisms that may alter the reproductive functions and lead to male subfertility in CLD patients, with a phenotype reminiscent of that induced by CFTR deficiency in the male genital tract.
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functional interaction of the cystic fibrosis transmembrane conductance regulator with members of the slc26 family of anion transporters slc26a8 and slc26a9 physiological and pathophysiological relevance
The International Journal of Biochemistry & Cell Biology, 2014Co-Authors: Elma El Khouri, Aminata ToureAbstract:The solute carrier 26 (SLC26) proteins are transmembrane proteins located at the plasma membrane of the cells and transporting a variety of monovalent and divalent anions, including chloride, bicarbonate, sulfate and oxalate. In humans, 11 members have been identified (SLC26A1 to SLC26A11) and although part of them display a very restricted tissue expression pattern, altogether they are widely expressed in the epithelial cells of the body where they contribute to the composition and the pH regulation of the secreted fluids. Importantly, mutations in SLC26A2, A3, A4, and A5 have been associated with distinct human genetic recessive disorders (i.e. diastrophic dysplasia, congenital chloride diarrhea, Pendred syndrome and deafness, respectively), demonstrating their essential and non-redundant functions in many tissues. During the last decade, physical and functional interactions of SLC26 members with the cystic fibrosis transmembrane conductance regulator (CFTR) have been highly documented, leading to the model of a crosstalk based on the binding of the SLC26 STAS domain to the CFTR regulatory domain. In this review, we will focus on the functional interaction of SLC26A8 and SLC26A9 with the CFTR channel. In particular we will highlight the newly published studies indicating that mutations in SLC26A8 and SLC26A9 proteins are associated with a deregulation of the CFTR anion transport activity in the pathophysiological context of the sperm and the pulmonary cells. These studies confirm the physiological relevance of SLC26 and CFTR cross-regulation, opening new gates for the treatment of cystic fibrosis.
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functional interaction of the cystic fibrosis transmembrane conductance regulator with members of the slc26 family of anion transporters slc26a8 and slc26a9 physiological and pathophysiological relevance
The International Journal of Biochemistry & Cell Biology, 2014Co-Authors: Elma El Khouri, Aminata ToureAbstract:Abstract The solute carrier 26 (SLC26) proteins are transmembrane proteins located at the plasma membrane of the cells and transporting a variety of monovalent and divalent anions, including chloride, bicarbonate, sulfate and oxalate. In humans, 11 members have been identified (SLC26A1 to SLC26A11) and although part of them display a very restricted tissue expression pattern, altogether they are widely expressed in the epithelial cells of the body where they contribute to the composition and the pH regulation of the secreted fluids. Importantly, mutations in SLC26A2 , A3 , A4 , and A5 have been associated with distinct human genetic recessive disorders ( i.e. diastrophic dysplasia, congenital chloride diarrhea, Pendred syndrome and deafness, respectively), demonstrating their essential and non-redundant functions in many tissues. During the last decade, physical and functional interactions of SLC26 members with the cystic fibrosis transmembrane conductance regulator (CFTR) have been highly documented, leading to the model of a crosstalk based on the binding of the SLC26 STAS domain to the CFTR regulatory domain. In this review, we will focus on the functional interaction of SLC26A8 and SLC26A9 with the CFTR channel. In particular we will highlight the newly published studies indicating that mutations in SLC26A8 and SLC26A9 proteins are associated with a deregulation of the CFTR anion transport activity in the pathophysiological context of the sperm and the pulmonary cells. These studies confirm the physiological relevance of SLC26 and CFTR cross-regulation, opening new gates for the treatment of cystic fibrosis. This article is part of a Directed Issue entitled: Cystic Fibrosis: From o-mics to cell biology, physiology, and therapeutic advances.
Juha Kere - One of the best experts on this subject based on the ideXlab platform.
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congenital chloride diarrhea and pendred syndrome case report of siblings with two rare recessive disorders of slc26 family genes
BMC Medical Genetics, 2020Co-Authors: Eva Lindberg, Juha Kere, Satu Wedenoja, Claes Moller, Agneta AnderzencarlssonAbstract:Congenital chloride diarrhea (CLD; OMIM 214700) is a rare autosomal recessive disorder caused by pathogenic variations in the solute carrier family 26 member A3 (SLC26A3) gene. Without salt substitution, this chronic diarrheal disorder causes severe dehydration and electrolyte disturbances. Homozygous variants in the nearby gene SLC26A4 disrupt anion exchange in the inner ear and the thyroid, causing Pendred syndrome (PDS; OMIM 274600), which is the most frequent form of syndromic deafness. We report an unusual co-occurrence of two rare homozygous mutations in both the SLC26A3 and SLC26A4 genes, causing a rare combination of both CLD and PDS in two siblings. Although the clinical pictures were typical, the combined loss of these anion transporters might modulate the risk of renal injury associated with CLD. Familial presentation of two rare autosomal recessive disorders with loss of function of different SLC26 anion transporters is described. Independent homozygous variants in the SLC26A3 and SLC26A4 genes cause CLD and PDS in siblings, shedding light on co-occurrence of rare recessive traits in the progeny of consanguineous couples.
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update on SLC26A3 mutations in congenital chloride diarrhea
Human Mutation, 2011Co-Authors: Satu Wedenoja, Juha Kere, Christer Holmberg, Pia Hoglund, Siru Makela, Elina PekansaariAbstract:Congenital chloride diarrhea (CLD) is an autosomal recessive disorder with around 250 cases reported so far. Life-long secretory diarrhea is caused by mutations in the solute carrier family 26 member 3 (SLC26A3) gene disrupting the epithelial Cl−/HCO transport in the ileum and colon. Although salt substitution allows favorable outcome, possible manifestations include renal impairment, intestinal inflammation, and male infertility. At least 55 mutations, of which 21 (38%) novel are reported here, cause CLD. Majority of the mutations are single nucleotide substitutions (n = 30; 55%) with 18 missense, 7 nonsense, and 5 splice-site mutations. Additional mutations are minor deletions/insertions or their combinations (n = 21; 38%), major deletions (n = 3; 5%), and a major insertion (n = 1; 2%). Distinct founder mutations appear in Finland, Poland, and Arab countries, whereas patients from other countries carry rare homozygous or compound heterozygous mutations. None of the studied SLC26A3 mutants shows significant Cl−/HCO exchange activity in vitro, and accordingly, evidence of genotype–phenotype differencies remain nonexistent. The domain interaction between SLC26A3 and the cystic fibrosis transmembrane conductance regulator (CFTR) raises a possibility of CFTR modulation in the pathogenesis of CLD. This review summarizes the current knowledge of SLC26A3 mutations and polymorphisms, and their biological and clinical relevance. Hum Mutat 32:1–8, 2011. © 2011 Wiley-Liss, Inc.
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expression of SLC26A3 cftr and nhe3 in the human male reproductive tract role in male subfertility caused by congenital chloride diarrhoea
Molecular Human Reproduction, 2006Co-Authors: Satu Hihnala, Minna Kujala, Jorma Toppari, Juha Kere, Christer Holmberg, Pia HoglundAbstract:Congenital chloride diarrhoea (CLD) is a rare inherited disease caused by mutations in the solute carrier family 26 member 3 (SLC26A3) gene. Disruption of intestinal Cl – /HCO 3 – exchange causes watery Cl – rich diarrhoea from birth, and recently male subfertility was observed as a novel manifestation. Expression of SLC26A3, together with interacting proteins cystic fibrosis transmembrane conductance regulator (CFTR) and Na + /H + exchanger 3 (NHE3), was studied using immunohistochemistry in the testis (n = 2) and efferent ducts (ED) (n = 1) of patients with CLD (V317del genotype) and in the testis and epididymis (n = 11), seminal vesicle (n = 9) and prostate (n = 4) of the controls. SLC26A3 was immunolocalized in the head of the elongating spermatids (stages III–VI) and CFTR in the elongating spermatids (stages III and IV) and pachytene (stages III–V) and diplotene spermatocytes. In the non-ciliated cells of the ED, apical expression of all three proteins was observed, but only SLC26A3 and CFTR were detected on the luminal border of the apical mitochondria-rich cells (AMRC) of the ductus epididymis and in the epithelium of the seminal vesicle. Only CFTR was present in the epithelium of the prostatic duct. In the patient with CLD, the expression of both SLC26A3 and CFTR was absent in the ED, but testicular expression was identical to that of the controls. These results suggest a primary role for SLC26A3 in male reproduction. Tissue-specific co-expression with CFTR and NHE3 supports diverse functions of SLC26A3 and may have an impact on pathophysiology of male subfertility both in CLD and in cystic fibrosis (CF), as well as spermatoceles.
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functional comparison of mouse slc26a6 anion exchanger with human slc26a6 polypeptide variants differences in anion selectivity regulation and electrogenicity
Journal of Biological Chemistry, 2005Co-Authors: Marina N Chernova, David H. Vandorpe, Juha Kere, Hannes Lohi, Lianwei Jiang, David J Friedman, Rachel B Darman, Seth L AlperAbstract:Abstract The unusually low 78% amino acid identity between the orthologous human SLC26A6 and mouse slc26a6 polypeptides prompted systematic comparison of their anion transport functions in Xenopus oocytes. Multiple human SLC26A6 variant polypeptides were also functionally compared. Transport was studied as unidirectional fluxes of 36Cl-, [14C]oxalate, and [35S]sulfate; as net fluxes of by fluorescence ratio measurement of intracellular pH; as current by two-electrode voltage clamp; and as net Cl- flux by fluorescence intensity measurement of relative changes in extracellular and intracellular [Cl-]. Four human SLC26A6 polypeptide variants each exhibited rates of bidirectional [14C]oxalate flux, exchange, and Cl-/OH- exchange nearly equivalent to those of mouse slc26a6. exchange by both orthologs was cAMP-sensitive, further enhanced by coexpressed wild type cystic fibrosis transmembrane regulator but inhibited by cystic fibrosis transmembrane regulator ΔF508. However, the very low rates of 36Cl- and [35S]sulfate transport by all active human SLC26A6 isoforms contrasted with the high rates of the mouse ortholog. Human and mouse orthologs also differed in patterns of acute regulation. Studies of human-mouse chimeras revealed cosegregation of the high 36Cl- transport phenotype with the transmembrane domain of mouse slc26a6. Mouse slc26a6 and human SLC26A6 each mediated electroneutral and Cl-/OH- exchange. In contrast, whereas Cl-/oxalate exchange by mouse slc26a6 was electrogenic, that mediated by human SLC26A6 appeared electroneutral. The increased currents observed in oocytes expressing either mouse or human ortholog were pharmacologically distinct from the accompanying monovalent anion exchange activities. The human SLC26A6 polypeptide variants SLC26A6c and SLC26A6d were inactive as transporters of oxalate, sulfate, and chloride. Thus, the orthologous mouse and human SLC26A6 proteins differ in anion selectivity, transport mechanism, and acute regulation, but both mediate electroneutral exchange.
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SLC26A3 mutations in congenital chloride diarrhea
Human Mutation, 2002Co-Authors: Siru Makela, Juha Kere, Christer Holmberg, Pia HoglundAbstract:Congenital chloride diarrhea (CLD) is an autosomal recessive disorder of intestinal electrolyte absorption. It is characterized by persistent secretory diarrhea resulting in polyhydramnios and prematurity prenatally, and dehydration, hypoelectrolytemia, hyperbilirubinemia, abdominal distention, and failure to thrive immediately after birth. CLD is caused by mutations in the solute carrier family 26, member 3 gene (SLC26A3, alias CLD or DRA), which encodes a Na+-independent Cl−/HCO3− (or OH−) exchanger. SLC26A3 is a member of the SLC26 sulfate permease/anion transporter family and it is expressed mainly in the apical brush border of intestinal epithelium. The only extraintestinal tissues showing SLC26A3 expression are eccrine sweat glands and seminal vesicles. A wide variety of different mutations in the SLC26A3 gene have been associated with CLD with no apparent evidence of phenotype–genotype correlation. The clinical course of CLD, however, is variable and may rather depend on environmental factors and compensatory mechanisms than mutations. In this report, we present a summary of all published and two novel SLC26A3 mutations and polymorphisms, and review them in the context of their functional consequences and clinical implications. Hum Mutat 20:425–438, 2002. © 2002 Wiley-Liss, Inc.
Nikolay Shcheynikov - One of the best experts on this subject based on the ideXlab platform.
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properties and function of the solute carrier 26 family of anion transporters
2016Co-Authors: Nikolay Shcheynikov, Ehud Ohana, Shmuel MuallemAbstract:The SLC26 family of anion transporters consists of 10 members that display remarkable functional and substrate diversity. Mutations in several members of the family have been identified as causing a variety of human diseases and mouse phenotype when deleted. The family drew the attention and strong interest of epithelial biologist with the identification of the first elusive luminal Cl−/HCO3− exchange, which turned to be the third member of the family SLC26A3. Fairly quick, progress since revealed that members of the family transport all halides, NO3−, SO42−, oxalate, and formate, among others. Members of the family can be grouped into three subgroups based on substrate selectivity and transport mode: the SO42− transporters SLC26A1 and SLC26A2; the anion exchangers 2Cl−/1HCO3− SLC26A3, 1Cl−/1HCO3− SLC26A4, and 1Cl−/2HCO3− SLC26A6; and the Cl− channels SLC26A7, SLC26A9, and SLC26A11. This chapter discusses structural features, transport properties, and regulation of the transporters that are essential to understand their functions and roles in human diseases.
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solute carrier family 26 member a2 slc26a2 protein functions as an electroneutral so42 oh cl exchanger regulated by extracellular cl
Journal of Biological Chemistry, 2012Co-Authors: Ehud Ohana, Nikolay Shcheynikov, Meeyoung Park, Shmuel MuallemAbstract:Slc26a2 is a ubiquitously expressed SO42− transporter with high expression levels in cartilage and several epithelia. Mutations in SLC26A2 are associated with diastrophic dysplasia. The mechanism by which Slc26a2 transports SO42− and the ion gradients that mediate SO42− uptake are poorly understood. We report here that Slc26a2 functions as an SO42−/2OH−, SO42−/2Cl−, and SO42−/OH−/Cl− exchanger, depending on the Cl− and OH− gradients. At inward Cl− and outward pH gradients (high Cl−o and low pHo) Slc26a2 functions primarily as an SO42−o/2OH−i exchanger. At low Cl−o and high pHo Slc26a2 functions increasingly as an SO42−o/2Cl−i exchanger. The reverse is observed for SO42−i/2OH−o and SO42−i/2Cl−o exchange. Slc26a2 also exchanges Cl− for I−, Br−, and NO3− and Cl−o competes with SO42− on the transport site. Interestingly, Slc26a2 is regulated by an extracellular anion site, required to activate SO42−i/2OH−o exchange. Slc26a2 can transport oxalate in exchange for OH− and/or Cl− with properties similar to SO42− transport. Modeling of the Slc26a2 transmembrane domain (TMD) structure identified a conserved extracellular sequence 367GFXXP371 between TMD7 and TMD8 close to the conserved Glu417 in the permeation pathway. Mutation of Glu417 eliminated transport by Slc26a2, whereas mutation of Phe368 increased the affinity for SO42−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 SO42− 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.
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diverse transport modes by the solute carrier 26 family of anion transporters
The Journal of Physiology, 2009Co-Authors: Ehud Ohana, Dongki Yang, Nikolay Shcheynikov, Shmuel MuallemAbstract:The solute carrier 26 (SLC26) transporters are anion transporters with diverse substrate specificity. Several members are ubiquitous while others show limited tissue distribution. They are expressed in many epithelia and to the extent known, play a central role in anion secretion and absorption. Members of the family are primarily Cl- transporters, although some members transport mainly SO(4)2-, Cl-, HCO(3)- or I-. A defining feature of the family is their functional diversity. Slc26a1 and Slc26a2 function as specific SO(4)2- transporters while Slc26a4 functions as an electroneutral Cl-/I-/HCO(3)- exchanger. SLC26A3 and Slc26a6 function as coupled electrogenic Cl-/HCO(3)- exchangers or as bona fide anion channels. SLC26A7 and SLC26A9 function exclusively as Cl- channels. This short review discusses the functional diversity of the SLC26 transporters.
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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
The Journal of Physiology, 2008Co-Authors: Nikolay Shcheynikov, Lawrence P. Karniski, Dongki Yang, Youxue Wang, Weizong Zeng, Insuk So, Susan M Wall, Shmuel MuallemAbstract:Transcellular Cl− and HCO3− 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−/HCO3− and Cl−/HCO3− 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 HCO3− transport. By contrast, Slc26a6 mediates luminal Cl−/HCO3− exchange activity with minimal role in I− secretion. Furthermore, silencing of CFTR altered Cl−/HCO3− 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.
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congenital chloride losing diarrhea causing mutations in the stas domain result in misfolding and mistrafficking of SLC26A3
Journal of Biological Chemistry, 2008Co-Authors: Michael R Dorwart, Nikolay Shcheynikov, Shmuel Muallem, Jennifer M R Baker, Julie D Formankay, Philip J ThomasAbstract:Congenital chloride-losing diarrhea (CLD) is a genetic disorder causing watery stool and dehydration. Mutations in SLC26A3 (solute carrier 26 family member 3), which functions as a coupled Cl(-)/HCO(3)(-) exchanger, cause CLD. SLC26A3 is a membrane protein predicted to contain 12 transmembrane-spanning alpha-helices and a C-terminal STAS (sulfate transporters and anti-sigma-factor) domain homologous to the bacterial anti-sigma-factor antagonists. The STAS domain is required for SLC26A3 Cl(-)/HCO(3)(-) exchange function and for the activation of cystic fibrosis transmembrane conductance regulator by SLC26A3. Here we investigate the molecular mechanism(s) by which four CLD-causing mutations (DeltaY526/7, I544N, I675/6ins, and G702Tins) in the STAS domain lead to disease. In a heterologous mammalian expression system biochemical, immunohistochemical, and ion transport experiments suggest that the four CLD mutations cause SLC26A3 transporter misfolding and/or mistrafficking. Expression studies with the isolated STAS domain suggest that the I675/6ins and G702Tins mutations disrupt the STAS domain directly, whereas limited proteolysis experiments suggest that the DeltaY526/7 and I544N mutations affect a later step in the folding and/or trafficking pathway. The data suggest that these CLD-causing mutations cause disease by at least two distinct molecular mechanisms, both ultimately leading to loss of functional protein at the plasma membrane.