Pendrin Is an Iodide-Specific Apical Porter Responsible for Iodide Efflux from Thyroid Cells

Yoshïda, Akio; Taniguchi, Shin‐ichi; Hisatome, Ichiro; Royaux, Ines; Green, Eric D.; Kohn, Leonard D.; Suzuki, Koichi

doi:10.1210/jcem.87.7.8679

Cited by 116 publications

(64 citation statements)

References 28 publications

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“…In thyroid follicular cells, pendrin was inserted into the apical membrane (28,29). The apical localization, together with the impaired iodide organification observed in patients with Pendred's syndrome and the previous demonstration of the ability of pendrin to transport iodide in oocyte or non-polarized cell systems, suggested a possible role in iodide transport into the thyroid follicle (3,10,28,30). Using a polarized cell system, the experiments presented here provides formal evidence that pendrin can mediate iodide efflux at the apical membrane (Fig.…”

Section: ) Similar Results Were Observed In Tsa-293 Cells (Results mentioning

confidence: 93%

“…The absence of bicarbonate secretion was also demonstrated in renal tubuli isolated from mice with targeted disruption of the Pds gene (25). More recently, studies performed in non-polarized mammalian cells proposed a role for pendrin in mediating iodide efflux (10,30).…”

Section: ) Similar Results Were Observed In Tsa-293 Cells (Results mentioning

confidence: 96%

“…Functional studies in transfected cells subsequently demonstrated that the protein can mediate iodide transport in mammalian cells (10,30). These findings, together with the impaired iodide organification in patients with Pendred's syndrome, suggest a possible role of pendrin in mediating apical iodide efflux from thyrocytes into the follicle.…”

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confidence: 98%

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Functional Characterization of Pendrin in a Polarized Cell System

Gillam

Sidhaye

Lee

et al. 2004

Journal of Biological Chemistry

144

110

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Pendred's syndrome is an autosomal recessive disorder characterized by sensorineural deafness, goiter, and impaired iodide organification. It is caused by mutations in the PDS/SLC26A4 gene that encodes pendrin. Functionally, pendrin is a transporter of chloride and iodide in Xenopus oocytes and heterologous mammalian cells and a chloride/base exchanger in ␤-intercalated cells of the renal cortical collecting duct. The partially impaired thyroidal iodide organification in Pendred's syndrome suggests a possible role of pendrin in iodide transport at the apical membrane of thyroid follicular cells, but experimental evidence for this concept is lacking. The iodide transport properties of pendrin were determined in polarized Madin-Darby canine kidney cells expressing the sodium iodide symporter (NIS), pendrin, or NIS and pendrin using a bicameral system-permitting measurement of iodide content in the basal, intracellular, and apical compartments. Moreover, we determined the functional consequences of two naturally occurring mutations (L676Q and FS306>309X). In polarized Madin-Darby canine kidney cells, NIS mediates uptake at the basolateral membrane. Only minimal amounts of iodide reach the apical compartment in the absence of pendrin. In cells expressing NIS and pendrin, pendrin mediates transport of iodide into the apical chamber. Wild type pendrin also mediates iodide efflux in transiently transfected cells. In contrast, both pendrin mutants lose the ability to promote iodide efflux. These results provide evidence that pendrin mediates apical iodide efflux from polarized mammalian cells loaded with iodide. Consistent with the partial organification defect observed in patients with Pendred's syndrome, naturally occurring mutations of pendrin lead to impaired transport of iodide.

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Section: ) Similar Results Were Observed In Tsa-293 Cells (Results mentioning

confidence: 93%

Section: ) Similar Results Were Observed In Tsa-293 Cells (Results mentioning

confidence: 96%

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Functional Characterization of Pendrin in a Polarized Cell System

Gillam

Sidhaye

Lee

et al. 2004

Journal of Biological Chemistry

144

110

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“…Iodide uptake and efflux were measured as previously described (31). COS7 cells (5 ϫ 10 4 /well) transiently transfected with pEGFP-C1-PDS for 48 h or NCI-H292 cells (5 ϫ 10 4 /well) incubated with 8 ϫ 10 5 CIU/well of SeV(HNL)-mPend/⌬F or SeV/⌬F (SeV 18ϩ GFP/⌬F) for 48 h were used.…”

Section: Transport Assay Of Iodidementioning

confidence: 99%

Identification of Pendrin as a Common Mediator for Mucus Production in Bronchial Asthma and Chronic Obstructive Pulmonary Disease

Nakao¹,

Kanaji²,

Ohta³

et al. 2008

The Journal of Immunology

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121

148

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Excessive production of airway mucus is a cardinal feature of bronchial asthma and chronic obstructive pulmonary disease (COPD) and contributes to morbidity and mortality in these diseases. IL-13, a Th2-type cytokine, is a central mediator in the pathogenesis of bronchial asthma, including mucus overproduction. Using a genome-wide search for genes induced in airway epithelial cells in response to IL-13, we identified pendrin encoded by the SLC26A4 (PDS) gene as a molecule responsible for airway mucus production. In both asthma and COPD mouse models, pendrin was up-regulated at the apical side of airway epithelial cells in association with mucus overproduction. Pendrin induced expression of MUC5AC, a major product of mucus in asthma and COPD, in airway epithelial cells. Finally, the enforced expression of pendrin in airway epithelial cells in vivo, using a Sendai virus vector, rapidly induced mucus overproduction in the lumens of the lungs together with neutrophilic infiltration in mice. These findings collectively suggest that pendrin can induce mucus production in airway epithelial cells and may be a therapeutic target candidate for bronchial asthma and COPD.

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“…The fluorometric method was described previously in detail (19,20). In brief, the SLC26A4 protein is able to transport chloride (19,29,30) as well as iodide (11,15,27,31,32), and therefore, because the EYFP protein is a fluorescent dye sensitive to intracellular halides, this dye is particularly suitable for sensing changes in the intracellular chloride as well as iodide amount, and therefore to measure the respective ion fluxes across the cell membrane. By changing the extracellular chloride or iodide concentration in cells over-expressing the SLC26A4 protein and comparing the result with the result obtained in cells not over-expressing SLC26A4, the transport contribution of SLC26A4 can be easily determined.…”

Section: Subjectsmentioning

confidence: 99%

Functional assessment of allelic variants in the SLC26A4 gene involved in Pendred syndrome and nonsyndromic EVA

Pera

Dossena

Rodighiero³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

105

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Pendred syndrome is an autosomal recessive disorder characterized by sensorineural hearing loss, with malformations of the inner ear, ranging from enlarged vestibular aqueduct (EVA) to Mondini malformation, and deficient iodide organification in the thyroid gland. Nonsyndromic EVA (ns-EVA) is a separate type of sensorineural hearing loss showing normal thyroid function. Both Pendred syndrome and ns-EVA seem to be linked to the malfunction of pendrin (SLC26A4), a membrane transporter able to exchange anions between the cytosol and extracellular fluid. In the past, the pathogenicity of SLC26A4 missense mutations were assumed if the mutations fulfilled two criteria: low incidence of the mutation in the control population and substitution of evolutionary conserved amino acids. Here we show that these criteria are insufficient to make meaningful predictions about the effect of these SLC26A4 variants on the pendrin-induced ion transport. Furthermore, we functionally characterized 10 missense mutations within the SLC26A4 ORF, and consistently found that on the protein level, an addition or omission of a proline or a charged amino acid in the SLC26A4 sequence is detrimental to its function. These types of changes may be adequate for predicting SLC26A4 functionality in the absence of direct functional tests.ion transport physiology ͉ genotype-phenotype correlation P endred syndrome (PS) (OMIM#274600) (1) is an autosomal recessive disorder characterized by sensorineural hearing loss (SNHL) and malformations of the inner ear, ranging from enlarged vestibular aqueduct (EVA) (2) to Mondini malformation (3), combined with deficient iodide organification in the thyroid gland, as demonstrated by the positive perchlorate discharge test in affected individuals (4-7). Another form of SNHL associated with EVA, however, showing normal thyroid function, is called nonsyndromic EVA (ns-EVA) (OMIM#600791). The clinical features of PS are the consequence of impaired pendrin function (1), a protein encoded by the SLC26A4 gene (NM 000441). It is a member of the multifunctional anion transporter family SLC26, which mediates the exchange of anions including Cl Ϫ , HCO 3 Ϫ , OH Ϫ , I Ϫ , or formate (8). Pendrin seems to be responsible for the efflux of iodide in thyrocytes (9-11), and for mediating Cl Ϫ /HCO 3 Ϫ exchange in the kidney cortex (12) and inner ear. In the latter, pendrin is involved in the conditioning of endolymphatic fluid, presumably because of HCO 3 Ϫ secretion (13), thereby modifying inner ear acid-base homeostasis. A variable feature of PS is the development of goitre (apparent in only about 50% of the affected individuals). At the thyroid level, the role of pendrin is not conclusive. The transporter could act as an iodide transporter at the apical membrane of thyroid cells and impaired function could therefore lead to the iodide organification defect observed in PS patients (10,11,(14)(15)(16). PS seems to be linked to bi-allelic mutations of the SLC26A4 genes. ns-EVA is genetically more heterogeneous relative to PS, and a...

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Pendrin Is an Iodide-Specific Apical Porter Responsible for Iodide Efflux from Thyroid Cells

Cited by 116 publications

References 28 publications

Functional Characterization of Pendrin in a Polarized Cell System

Functional Characterization of Pendrin in a Polarized Cell System

Identification of Pendrin as a Common Mediator for Mucus Production in Bronchial Asthma and Chronic Obstructive Pulmonary Disease

Functional assessment of allelic variants in the SLC26A4 gene involved in Pendred syndrome and nonsyndromic EVA

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