TSH Regulates Pendrin Membrane Abundance and Enhances Iodide Efflux in Thyroid Cells

Pesce, Liuska; Bizhanova, Aigerim; Caraballo, Juan C.; Westphal, Whitney; Butti, Maria L.; Comellas, Alejandro P.; Kopp, Peter

doi:10.1210/en.2011-1548

Cited by 48 publications

(56 citation statements)

References 41 publications

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“…Thus, while increase of intracellular calcium concentration does not affect pendrin-mediated iodide efflux, it greatly stimulates iodide release from ANO1-expressing HEK 293T cells, PCCl3 cells, and dog thyrocytes. Of note, Pesce et al (27) showed weak activation of iodide loss by TSH but not by forskolin in PCCl3 cells, which suggests a TSH effect through the weakly responding phospholipase C-PIP 2 …”

Section: Concentration In Pccl3 Cells and In Ano1-expressing Hek 293tmentioning

confidence: 95%

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: Concentration In Pccl3 Cells and In Ano1-expressing Hek 293tmentioning

confidence: 95%

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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“…It is well known that TSH induces the expression of many genes involved in TH biosynthesis, particularly the expression of Pds and Nis and, to a lesser extent, that of Tpo and Duoxa2 (6,7,9,10,43). Since TSH levels are greatly elevated in Glis3KO mice, one might surmise that these genes are expressed at significantly higher levels in Glis3KO compared with WT mice.…”

Section: 2mentioning

confidence: 99%

“…Interaction of TSH with the TSH receptor (TSHR), a G proteincoupled receptor (Gα q /Gα 11 ), leads to activation of several kinase signaling cascades, including PKA, PKC, AMPK, and the PI3K/ mTOR complex 1 (mTORC1) pathways (2)(3)(4)(5)(6)(7)(8). Through these pathways, TSH regulates the expression of genes that are associated with thyroid gland development and TH biosynthesis and secretion, including thyroid peroxidase (TPO), and the Na + /I -symporter (NIS; SLC5A5) and iodide transporter pendrin (PDS, also referred to as SLC26A4) (7,9,10). Prolonged TSH stimulation causes proliferation of thyroid follicular cells, leading to enlargement of the thyroid gland (goiter) (6,8,11).…”

Section: Introductionmentioning

confidence: 99%

GLIS3 is indispensable for TSH/TSHR-dependent thyroid hormone biosynthesis and follicular cell proliferation

Kang¹,

Kumar²,

Liao³

et al. 2017

Journal of Clinical Investigation

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“…Using Thyr-IL-4 transgenic mice, this study showed for the first time an IL-4-dependent induction of Slc26a4 transcription, which was associated with increased apical expression of pendrin. TSH can rapidly stimulate pendrin membrane translocation via the PKA pathway (65), although the Thyr-IL-4 mice showed no significant increase in serum TSH level relative to WT mice (Fig. 2B).…”

Section: Discussionmentioning

confidence: 96%

Overexpression of Interleukin-4 in the Thyroid of Transgenic Mice Upregulates the Expression ofDuox1and the Anion Transporter Pendrin

Eskalli

Achouri

Hahn

et al. 2016

Thyroid

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Background:The dual oxidases (Duox) are involved in hydrogen peroxide generation, which is essential for thyroid hormone synthesis, and therefore they are markers of thyroid function. During inflammation, cytokines upregulate DUOX gene expression in the airway and the intestine, suggesting a role for these proteins in innate immunity. It was previously demonstrated that interleukin-4 (IL-4) upregulates DUOX gene expression in thyrocytes. Although the role of IL-4 in autoimmune thyroid diseases has been studied extensively, the effects of IL-4 on thyroid physiology remain largely unknown. Therefore, a new animal model was generated to study the impact of IL-4 on thyroid function. Methods: Transgenic (Thyr-IL-4) mice with thyroid-targeted expression of murine IL-4 were generated. Transgene expression was verified at the mRNA and protein level in thyroid tissues and primary cultures. The phenotype of the Thyr-IL-4 animals was characterized by measuring serum thyroxine (T4) and thyrotropin levels and performing thyroid morphometric analysis, immunohistochemistry, whole transcriptome sequencing, quantitative reverse transcription polymerase chain reaction, and ex vivo thyroid function assays. Results: Thyrocytes from two Thyr-IL-4 mouse lines (#30 and #52) expressed IL-4, which was secreted into the extracellular space. Although 10-month-old transgenic animals had T4 and thyrotropin serum levels in the normal range, they had altered thyroid follicular structure with enlarged follicles composed of elongated thyrocytes containing numerous endocytic vesicles. These follicles were positive for T4 staining the colloid, indicating their capacity to produce thyroid hormones. RNA profiling of Thyr-IL-4 thyroid samples revealed modulation of multiple genes involved in inflammation, while no major leukocyte infiltration could be detected. Upregulated expression of Duox1, Duoxa1, and the pendrin anion exchanger gene (Slc26a4) was detected. In contrast, the iodide symporter gene Slc5a5 was markedly downregulated resulting in impaired iodide uptake and reduced thyroid hormone levels in transgenic thyroid tissue. Hydrogen peroxide production was increased in Thyr-IL-4 thyroid tissue compared with wild-type animals, but no significant oxidative stress could be detected. Conclusions: This is the first study to show that ectopic expression of IL-4 in thyroid tissue upregulates Duox1/ Duoxa1 and Slc26a4 expression in the thyroid. The present data demonstrate that IL-4 could affect thyroid morphology and function, mainly by downregulating Slc5a5 expression, while maintaining a normal euthyroid phenotype.

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TSH Regulates Pendrin Membrane Abundance and Enhances Iodide Efflux in Thyroid Cells

Cited by 48 publications

References 41 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

GLIS3 is indispensable for TSH/TSHR-dependent thyroid hormone biosynthesis and follicular cell proliferation

Overexpression of Interleukin-4 in the Thyroid of Transgenic Mice Upregulates the Expression ofDuox1and the Anion Transporter Pendrin

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