The Na
            <sup>+</sup>
            /I
            <sup>−</sup>
            symporter (NIS) mediates electroneutral active transport of the environmental pollutant perchlorate

Dohán, Orsolya; Portulano, Carla; Basquin, Cécile; Reyna-Neyra, Andrea; Amzel, L. Mario; Carrasco, Nancy

doi:10.1073/pnas.0707207104

Cited by 161 publications

(147 citation statements)

References 41 publications

(100 reference statements)

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“…I − transport mediated by NIS is electrogenic, with a 2 Na + : 1 I − stoichiometry (4). Other anions, such as perrhenate (ReO 4 − ) (5) and the environmental pollutant perchlorate (ClO 4 − ) (6), are also transported by NIS, but, surprisingly, with an electroneutral (1 Na + : 1 anion) stoichiometry. Besides the thyroid, NIS mediates active I − transport in several other tissues, including the lactating breast (7), salivary glands (7,8), stomach (9), and small intestine (10,11).…”

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confidence: 99%

Na ⁺ coordination at the Na2 site of the Na ⁺ /I ⁻ symporter

Ferrandino

Nicola

Sánchez

et al. 2016

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

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The sodium/iodide symporter (NIS) mediates active I− transport in the thyroid—the first step in thyroid hormone biosynthesis—with a 2 Na+: 1 I− stoichiometry. The two Na+ binding sites (Na1 and Na2) and the I− binding site interact allosterically: when Na+ binds to a Na+ site, the affinity of NIS for the other Na+ and for I− increases significantly. In all Na+-dependent transporters with the same fold as NIS, the side chains of two residues, S353 and T354 (NIS numbering), were identified as the Na+ ligands at Na2. To understand the cooperativity between the substrates, we investigated the coordination at the Na2 site. We determined that four other residues—S66, D191, Q194, and Q263—are also involved in Na+ coordination at this site. Experiments in whole cells demonstrated that these four residues participate in transport by NIS: mutations at these positions result in proteins that, although expressed at the plasma membrane, transport little or no I−. These residues are conserved throughout the entire SLC5 family, to which NIS belongs, suggesting that they serve a similar function in the other transporters. Our findings also suggest that the increase in affinity that each site displays when an ion binds to another site may result from changes in the dynamics of the transporter. These mechanistic insights deepen our understanding not only of NIS but also of other transporters, including many that, like NIS, are of great medical relevance.

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confidence: 99%

Na ⁺ coordination at the Na2 site of the Na ⁺ /I ⁻ symporter

Ferrandino

Nicola

Sánchez

et al. 2016

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

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“…Particularly with regard to the diminished growth of PER-induced goiters, our data suggest that induction of PER-specific cellular stress responses might play an important role in the amphibian thyroid, including an up-regulation of negative growth regulators and de-regulation of genes with putative function in linking stress signalling and proliferative activity. Based on these findings, the important question arises whether the effects pattern observed in PER-treated tadpoles is primarily due to inhibition of iodide uptake, and thus represent a mode of actionspecific response, or caused by increased intracellular levels of PER (Dohan et al, 2007). In order to identify expression profiles that are unique for certain modes of goitrogen action, further comparative analyses of expression profiles are currently performed for diverse inhibitors of NIS and TPO.…”

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confidence: 99%

Perchlorate and ethylenethiourea induce different histological and molecular alterations in a non-mammalian vertebrate model of thyroid goitrogenesis

Opitz

Schmidt

Braunbeck

et al. 2009

Molecular and Cellular Endocrinology

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Despite evidence for a conserved role of thyroid-stimulating hormone (TSH) in regulating vertebrate thyroid function, molecular data on thyroid responses to TSH are mainly limited to mammalian species. In this study, we examined histological and molecular changes in the thyroid of Xenopus laevis tadpoles during a 12-day treatment with 20 mg/l perchlorate (PER) and 50 mg/l ethylenethiourea (ETU). Inhibition of thyroid hormone (TH) synthesis by PER and ETU was evident from developmental retardation, reduced expression of TH-regulated genes and up-regulation of tshb-A mRNA. Thyroid histopathology revealed goiters with strikingly different follicular morphologies following PER and ETU treatment. Using real-time PCR, we analyzed thyroids sampled on day 12 for differential expression of 60 candidate genes. Further temporal analyses were performed for a subset of 14 genes. Relative to the control, PER and ETU treatment modulated the expression of 51 and 49 transcripts, respectively. Particularly genes related to TH synthesis and protein metabolism were similarly affected by PER and ETU.However, several genes were differentially expressed in PER-and ETU-treated tadpoles.Specifically, goiter formation in the PER treatment was associated with low expression of genes related to DNA replication but high expression of negative growth regulators. Results from this work provide for the first time a characterization of gene expression profiles during goitrogenesis in a non-mammalian vertebrate model. Overall, our data suggest that, in addition to TSH over-stimulation, further mechanisms related to the mode of goitrogen action contribute to the regulation of thyroid gene expression.

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“…NIS-mediated I − transport is electrogenic: Two Na þ ions are transported with each I − (2). Remarkably, NIS translocates different substrates with different stoichiometries, as NIS-mediated transport of perrhenate (ReO 4 − ) or perchlorate (ClO 4 − ) is electroneutral (1Na þ ∶1ReO 4 − ∕ClO 4 − ) (3).…”

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Mechanism of anion selectivity and stoichiometry of the Na ⁺ /I ^- symporter (NIS)

Paroder-Belenitsky¹,

Maestas

Dohán³

et al. 2011

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

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I − uptake in the thyroid, the first step in thyroid hormone biosynthesis, is mediated by the Na þ ∕I − symporter (NIS) with an electrogenic 2Na þ : 1I − stoichiometry. We have obtained mechanistic information on NIS by characterizing the congenital I − transport defect-causing NIS mutant G93R. This mutant is targeted to the plasma membrane but is inactive. Substitutions at position 93 show that the longer the side chain of the neutral residue at this position, the higher the K m for the anion substrates. Unlike WT NIS, which mediates symport of Na þ and the environmental pollutant perchlorate electroneutrally, G93T/N/Q/E/D NIS, strikingly, do it electrogenically with a 2∶1 stoichiometry. Furthermore, G93E/Q NIS discriminate between anion substrates, a discovery with potential clinical relevance. A 3D homology model of NIS based on the structure of the bacterial Na þ ∕galactose transporter identifies G93 as a critical player in the mechanism of the transporter: the changes from an outwardly to an inwardly open conformation during the transport cycle use G93 as a pivot.iodide transport defect | homology modeling | radioiodide therapy | sodium solute cotransporter family

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The Na ⁺ /I ⁻ symporter (NIS) mediates electroneutral active transport of the environmental pollutant perchlorate

Cited by 161 publications

References 41 publications

Na ⁺ coordination at the Na2 site of the Na ⁺ /I ⁻ symporter

Na ⁺ coordination at the Na2 site of the Na ⁺ /I ⁻ symporter

Perchlorate and ethylenethiourea induce different histological and molecular alterations in a non-mammalian vertebrate model of thyroid goitrogenesis

Mechanism of anion selectivity and stoichiometry of the Na ⁺ /I ^- symporter (NIS)

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The Na + /I − symporter (NIS) mediates electroneutral active transport of the environmental pollutant perchlorate

Cited by 161 publications

References 41 publications

Na + coordination at the Na2 site of the Na + /I − symporter

Na + coordination at the Na2 site of the Na + /I − symporter

Perchlorate and ethylenethiourea induce different histological and molecular alterations in a non-mammalian vertebrate model of thyroid goitrogenesis

Mechanism of anion selectivity and stoichiometry of the Na + /I - symporter (NIS)

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The Na ⁺ /I ⁻ symporter (NIS) mediates electroneutral active transport of the environmental pollutant perchlorate

Na ⁺ coordination at the Na2 site of the Na ⁺ /I ⁻ symporter

Na ⁺ coordination at the Na2 site of the Na ⁺ /I ⁻ symporter

Mechanism of anion selectivity and stoichiometry of the Na ⁺ /I ^- symporter (NIS)