The Experts below are selected from a list of 154022091 Experts worldwide ranked by ideXlab platform
Shmuel Muallem - One of the best experts on this subject based on the ideXlab platform.
-
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.
-
multiple roles of the so42 cl oh exchanger protein SLC26A2 in chondrocyte functions
Journal of Biological Chemistry, 2014Co-Authors: Meeyoung Park, Ehud Ohana, Soo Young Choi, Myeongsok Lee, Jong Hoon Park, Shmuel MuallemAbstract:Mutations in the SO42−/Cl−/OH− exchanger SLC26A2 cause the disease diastrophic dysplasia (DTD), resulting in aberrant bone development and, therefore, skeletal deformities. DTD is commonly attributed to a lack of chondrocyte SO42− uptake and proteoglycan sulfation. However, the skeletal phenotype of patients with DTD is typified by reduction in cartilage and osteoporosis of the long bones. Chondrocytes of patients with DTD are irregular in size and have a reduced capacity for proliferation and terminal differentiation. This raises the possibility of additional roles for SLC26A2 in chondrocyte function. Here, we examined the roles of SLC26A2 in chondrocyte biology using two distinct systems: mouse progenitor mesenchymal cells differentiated to chondrocytes and freshly isolated mouse articular chondrocytes differentiated into hypertrophic chondrocytes. SLC26A2 expression was manipulated acutely by delivery of SLC26A2 or shSLC26A2 with lentiviral vectors. We demonstrate that SLC26A2 is essential for chondrocyte proliferation and differentiation and for proteoglycan synthesis. SLC26A2 also regulates the terminal stage of chondrocyte cell size expansion. These findings reveal multiple roles for SLC26A2 in chondrocyte biology and emphasize the importance of SLC26A2-mediated protein sulfation in cell signaling, which may account for the complex phenotype of DTD.
-
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.
-
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.
-
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.
Aminata Toure - One of the best experts on this subject based on the ideXlab platform.
-
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.
-
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.
-
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.
-
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.
-
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.
Nikolay Shcheynikov - One of the best experts on this subject based on the ideXlab platform.
-
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.
-
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.
-
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.
-
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.
-
slc26a6 regulates cftr activity in vivo to determine pancreatic duct hco3 secretion relevance to cystic fibrosis
The EMBO Journal, 2006Co-Authors: Youxue Wang, Nikolay Shcheynikov, Michael R Dorwart, Philip J Thomas, Abigail A Soyombo, Weizhong Zeng, Christopher R Marino, Shmuel MuallemAbstract:Fluid and HCO3− secretion are vital functions of the pancreatic duct and other secretory epithelia. CFTR and Cl−/HCO3− exchange activity at the luminal membrane are required for these functions. The molecular identity of the Cl−/HCO3− exchangers and their relationship with CFTR in determining fluid and HCO3− secretion are not known. We show here that the Cl−/HCO3− exchanger slc26a6 controls CFTR activity and ductal fluid and HCO3− secretion. Unexpectedly, deletion of slc26a6 in mice and measurement of fluid and HCO3− secretion into sealed intralobular pancreatic ducts revealed that deletion of slc26a6 enhanced spontaneous and decreased stimulated secretion. Remarkably, inhibition of CFTR activity with CFTRinh-172, knock-down of CFTR by siRNA and measurement of CFTR current in WT and slc26a6−/− duct cells revealed that deletion of slc26a6 resulted in dis-regulation of CFTR activity by removal of tonic inhibition of CFTR by slc26a6. These findings reveal the intricate regulation of CFTR activity by slc26a6 in both the resting and stimulated states and the essential role of slc26a6 in pancreatic HCO3− secretion in vivo.
Juha Kere - One of the best experts on this subject based on the ideXlab platform.
-
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.
-
expression of ion transport associated proteins in human efferent and epididymal ducts
Reproduction, 2007Co-Authors: Minna Kujala, Juha Kere, Satu Hihnala, Jukka Tienari, Kari Kaunisto, Johanna Hastbacka, Christer Holmberg, Pia HoglundAbstract:Appropriate intraluminal microenvironment in the epididymis is essential for maturation of sperm. To clarify whether the anion transporters SLC26A2, SLC26A6, SLC26A7, and SLC26A8 might participate in generating this proper intraluminal milieu, we studied the localization of these proteins in the human efferent and the epididymal ducts by immunohistochemistry. In addition, immunohistochemistry of several SLC26-interacting proteins was performed: the Na(+)/H(+) exchanger 3 (NHE3), the Cl(-) channel cystic fibrosis transmembrane conductance regulator (CFTR), the proton pump V-ATPase, their regulator Na(+)/H(+) exchanger regulating factor 1 (NHERF-1), and carbonic anhydrase II (CAII). Our results show that SLC26A6, CFTR, NHE3, and NHERF-1 are co-expressed on the apical side of the nonciliated cells, and SLC26A2 appears in the cilia of the ciliated cells in the human efferent ducts. In the epididymal ducts, SLC26A6, CFTR, NHERF-1, CAII, and V-ATPase (B and E subunits) were co-localized to the apical mitochondria rich cells, while SLC26A7 was expressed in a subgroup of basal cells. SLC26A8 was not found in the structures studied. This is the first study describing the localization of SLC26A2, A6 and A7, and NHERF-1 in the efferent and the epididymal ducts. Immunolocalization of human CFTR, NHE3, CAII, and V-ATPase in these structures differs partly from previous reports from rodents. Our findings suggest roles for these proteins in male fertility, either independently or through interaction and reciprocal regulation with co-localized proteins shown to affect fertility, when disrupted.
-
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.
-
SLC26A2 diastrophic dysplasia sulfate transporter is expressed in developing and mature cartilage but also in other tissues and cell types
Journal of Histochemistry and Cytochemistry, 2001Co-Authors: Siru Haila, Juha Kere, Johanna Hastbacka, Tom Bohling, Marjaliisa Karjalainen Lindsberg, Ulpu Saarialho KereAbstract:Mutated alleles of the SLC26A2 (diastrophic dysplasia sulfate transporter or DTDST) gene cause each of the four recessive chondrodysplasias, i.e., diastrophic dysplasia (DTD), multiple epiphyseal dysplasia (MED), atelosteogenesis Type II (AO2), and achondrogenesis Type IB (ACG1B). SLC26A2 acts as an Na+-independent sulfate/chloride antiporter and belongs to the SLC26 anion transporter gene family, currently consisting of six homologous human members. Although Northern analysis has indicated some expression in all tissues studied, the only tissue known to be affected by SLC26A2 mutations is cartilage. Abundant SLC26A2 expression has previously been detected in normal human colon by in situ hybridization. We have used in situ hybridization and immunohistochemistry to examine multiple normal tissues for the expression of human SLC26A2. As expected, a strong signal for SLC26A2 mRNA and protein immunostaining were detected in developing fetal hyaline cartilage, while bronchial cartilage showed mRNA expression ...
-
mapping of five new putative anion transporter genes in human and characterization of slc26a6 a candidate gene for pancreatic anion exchanger
Genomics, 2000Co-Authors: Hannes Lohi, Minna Kujala, Erja Kerkela, Ulpu Saarialhokere, Marjo Kestila, Juha KereAbstract:Abstract A second distinct family of anion transporters, in addition to the classical SLC4 (or AE) family, has recently been delineated. Members of the SLC26 family are structurally well conserved and can mediate the electroneutral exchange of Cl − for HCO − 3 across the plasma membrane of mammalian cells like members of the SLC4 family. Three human transporter proteins have been functionally characterized: SLC26A2 (DTDST), SLC26A3 (CLD or DRA), and SLC26A4 (PDS) can transport with different specificities the chloride, iodine, bicarbonate, oxalate, and hydroxyl anions, whereas SLC26A5 (prestin) was suggested to act as the motor protein of the cochlear outer hair cell. We report the expansion of the SLC26 family with five new members in chromosomes 3, 6, 8, 12, and 17 and mapping of SLC26A1 to 4p16.3. We have characterized one of them, SLC26A6, in more detail. It maps to chromosome 3p21.3, encodes a predicted 738-amino-acid transmembrane protein, and is most abundantly expressed in the kidney and pancreas. Pancreatic ductal cell lines Capan-1 and Capan-2 express SLC26A6, and immunohistochemistry localizes SLC26A6 protein to the apical surface of pancreatic ductal cells, suggesting it as a candidate for a luminal anion exchanger. The functional characterization of the novel members of this tissue-specific gene family may provide new insights into anion transport physiology in different parts of the body.