Pendred syndrome and iodide transport in the thyroid

Kopp, Peter; Pesce, Liuska; Solís-S, Juan Carlos

doi:10.1016/j.tem.2008.07.001

Cited by 105 publications

(82 citation statements)

References 71 publications

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“…11), thereby highlighting the conserved role of ANO1 in human. We confirm that pendrin is also able to export iodide from the cells as previously reported (12,18,36). Moreover, pendrin is present at the apex of thyroid cells and iodide release from a thyroid cell line derived from a Pendred patient is decreased (25).…”

Section: Discussionsupporting

confidence: 90%

“…The latter has been ascribed to the apical Cl Ϫ /HCO 3 Ϫ (I Ϫ ) exchanger pendrin. However, there are several arguments against an exclusive role of pendrin: 1) in human congenital homozygotic defects of pendrin (the Pendred syndrome), hypothyroidism only appears in iodine-deficient areas (18,25); and 2) the inactivation of pendrin gene in mouse does not induce a thyroid-deficient phenotype (6). The question therefore arises whether other membrane proteins fulfill this role.…”

Section: Discussionmentioning

confidence: 99%

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Anoctamin-1/TMEM16A is the major apical iodide channel of the thyrocyte

Twyffels

Strickaert

Virreira

et al. 2014

American Journal of Physiology-Cell Physiology

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Iodide is captured by thyrocytes through the Na ϩ /I Ϫ symporter (NIS) before being released into the follicular lumen, where it is oxidized and incorporated into thyroglobulin for the production of thyroid hormones. Several reports point to pendrin as a candidate protein for iodide export from thyroid cells into the follicular lumen. Here, we show that a recently discovered Ca 2ϩ -activated anion channel, TMEM16A or anoctamin-1 (ANO1), also exports iodide from rat thyroid cell lines and from HEK 293T cells expressing human NIS and ANO1. The Ano1 mRNA is expressed in PCCl3 and FRTL-5 rat thyroid cell lines, and this expression is stimulated by thyrotropin (TSH) in rat in vivo, leading to the accumulation of the ANO1 protein at the apical membrane of thyroid follicles. Moreover, ANO1 properties, i.e., activation by intracellular calcium (i.e., by ionomycin or by ATP), low but positive affinity for pertechnetate, and nonrequirement for chloride, better fit with the iodide release characteristics of PCCl3 and FRTL-5 rat thyroid cell lines than the dissimilar properties of pendrin. Most importantly, iodide release by PCCl3 and FRTL-5 cells is efficiently blocked by T16A inh-A01, an ANO1-specific inhibitor, and upon ANO1 knockdown by RNA interference. Finally, we show that the T16A inh-A01 inhibitor efficiently blocks ATP-induced iodide efflux from in vitro-cultured human thyrocytes. In conclusion, our data strongly suggest that ANO1 is responsible for most of the iodide efflux across the apical membrane of thyroid cells.anoctamin-1; iodide release; pendrin; thyrocyte; TMEM16A

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Anoctamin-1/TMEM16A is the major apical iodide channel of the thyrocyte

Twyffels

Strickaert

Virreira

et al. 2014

American Journal of Physiology-Cell Physiology

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“…Two previously characterized genes aside from NIS may be responsible for this phenomenon [26]. The first of these is SLC26A4, which encodes for the pendrin (PDS) expressed in apical membranes and has been suggested to transfer iodide into the colloid from the cells.…”

Section: Discussionmentioning

confidence: 99%

The Effect of Tanespimycin (17-AAG) on Radioiodine Accumulation in Sodium-Iodide Symporter Expressing Cells

Youn

Song

et al. 2012

Nucl Med Mol Imaging

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Purpose The heat shock protein 90 inhibitor, tanespimycin, is an anticancer agent known to increase iodine accumulation in normal and cancerous thyroid cells. Iodine accumulation is regulated by membrane proteins such as sodium iodide symporter (NIS) and pendrin (PDS), and thus we attempted to characterize the effects of tanespimycin on those genes. Methods Cells were incubated with tanespimycin in order to evaluate 125 I accumulation and efflux ability. Radioiodine uptake and efflux were measured by a gamma counter and normalized by protein amount. RT-PCR were performed to measure the level of gene expression. Results After tanespimycin treatment, 125 I uptake was increased by ∼2.5-fold in FRTL-5, hNIS-ARO, and hNIS-MDA-MB-231 cells, but no changes were detected in the hNIS-HeLa cells. Tanespimycin significantly reduced the radioiodine efflux rate only in the FRTL-5 cells. In the FRTL-5 and hNIS-ARO cells, PDS mRNA levels were markedly reduced; the only other observed alteration in the levels of NIS mRNA after tanespimycin treatment was an observed increase in the hNIS-ARO cells. Conclusions These results indicate that cellular responses against tanespimycin treatment differed between the normal rat thyroid cells and human cancer cells, and the reduction in the 125 I efflux rate by tanespimycin in the normal rat thyroid cells might be attributable to reduced PDS gene expression.

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“…However, the mechanisms linking pendrin loss of function to hearing impairment remain unclear. In the thyroid pendrin is expressed on the apical membrane of follicular cells, where it facilitates I 2 efflux into the follicle colloid for thyroid hormone synthesis (2,15). In the kidney pendrin is expressed in the apical plasma membrane of type B and non-A/non-B intercalated cells, where it facilitates Cl 2 absorption and HCO 3 2 secretion, ABBREVIATIONS: ASL, airway surface liquid; CaCC, calcium-activated chloride channel; CF, cystic fibrosis; CFBE, human cystic fibrosis bronchial epithelial; CFTR, cystic fibrosis transmembrane conductance regulator; ENaC, epithelial sodium channel; EYFP-HIF, enhanced yellow fluorescent protein-H148Q/I152L/F46L; FRT, Fischer rat thyroid; HBE, human bronchial epithelial; IC 50 , drug concentration causing 50% inhibition; I sc , short-circuit current; PCL, periciliary layer; UCSF, University of California, San Francisco; YFP, yellow fluorescent protein although kidney abnormalities are rare in Pendred syndrome (4,6,16).…”

mentioning

confidence: 99%

Inhibitors of pendrin anion exchange identified in a small molecule screen increase airway surface liquid volume in cystic fibrosis

Haggie

Phuan²,

Tan³

et al. 2016

FASEB j.

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Pendrin (SLC26A4) is a Cl 2 /anion exchanger expressed in the epithelium of inflamed airways where it is thought to facilitate Cl 2 absorption and HCO 3 2 secretion. Studies using pendrin knockout mice and airway epithelial cells from hearing-impaired subjects with pendrin loss of function suggest involvement of pendrin in inflammatory lung diseases, including cystic fibrosis (CF), perhaps by regulation of airway surface liquid (ASL) volume. Here we identified small-molecule pendrin inhibitors and demonstrated their efficacy in increasing ASL volume. A cell-based, functional high-throughput screen of ∼36,000 synthetic small molecules produced 3 chemical classes of inhibitors of human pendrin. After structure-activity studies, tetrahydropyrazolopyridine and pyrazolothiophenesulfonamide compounds reversibly inhibited pendrin-facilitated Cl 2 exchange with SCN 2 , I 2 , NO 3 2 , and HCO 3 2 with drug concentration causing 50% inhibition down to ∼2.5 mM. In well-differentiated primary cultures of human airway epithelial cells from non-CF and CF subjects, treatment with IL-13, which causes inflammation with strong pendrin up-regulation, strongly increased Cl 2 /HCO 3 2 exchange and the increase was blocked by pendrin inhibition. Pendrin inhibition significantly increased ASL depth (by ∼8 mm) in IL-13-treated non-CF and CF cells but not in untreated cells. These studies implicate the involvement of pendrin-facilitated Cl 2 / HCO 3 2 in the regulation of ASL volume and suggest the utility of pendrin inhibitors in inflammatory lung diseases, including CF

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Pendred syndrome and iodide transport in the thyroid

Cited by 105 publications

References 71 publications

Anoctamin-1/TMEM16A is the major apical iodide channel of the thyrocyte

Anoctamin-1/TMEM16A is the major apical iodide channel of the thyrocyte

The Effect of Tanespimycin (17-AAG) on Radioiodine Accumulation in Sodium-Iodide Symporter Expressing Cells

Inhibitors of pendrin anion exchange identified in a small molecule screen increase airway surface liquid volume in cystic fibrosis

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