Sodium-iodide symporter

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Solute carrier family 5 (sodium iodide symporter), member 5
Identifiers
SymbolsSLC5A5; NIS; TDH1
External IDsOMIM601843 MGI2149330 HomoloGene37311 GeneCards: SLC5A5 Gene
RNA expression pattern
PBB GE SLC5A5 211123 at tn.png
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez6528114479
EnsemblENSG00000105641ENSMUSG00000000792
UniProtQ92911Q99PN0
RefSeq (mRNA)NM_000453.2NM_053248.2
RefSeq (protein)NP_000444.1NP_444478.2
Location (UCSC)Chr 19:
17.98 – 18.01 Mb
Chr 8:
70.88 – 70.89 Mb
PubMed search[1][2]
 
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Solute carrier family 5 (sodium iodide symporter), member 5
Identifiers
SymbolsSLC5A5; NIS; TDH1
External IDsOMIM601843 MGI2149330 HomoloGene37311 GeneCards: SLC5A5 Gene
RNA expression pattern
PBB GE SLC5A5 211123 at tn.png
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez6528114479
EnsemblENSG00000105641ENSMUSG00000000792
UniProtQ92911Q99PN0
RefSeq (mRNA)NM_000453.2NM_053248.2
RefSeq (protein)NP_000444.1NP_444478.2
Location (UCSC)Chr 19:
17.98 – 18.01 Mb
Chr 8:
70.88 – 70.89 Mb
PubMed search[1][2]

The sodium/iodide symporter (NIS), also known as Sodium/iodide cotransporter[1] or solute carrier family 5, member 5 (SLC5A5) is a protein that in humans is encoded by the SLC5A5 gene.[2][3][4] The sodium/iodide symporter is a transmembrane glycoprotein with a molecular weight of 87 kDa and 13 transmembrane domains, which transports two sodium cations (Na+) for each iodide anion (I) into the cell.[5] NIS mediated uptake of iodide into follicular cells of the thyroid gland is the first step in the synthesis of thyroid hormone.[5]

Contents

Iodine uptake

Iodine uptake mediated by thyroid follicular cells from the blood plasma is the first step for the synthesis of thyroid hormones. This ingested iodine is bound to serum proteins, especially to albumins.[citation needed] The rest of the iodine which remains unlinked and free in bloodstream, is removed from the body through urine (the kidney is essential in te removal of iodine from extracellular space).

Iodine uptake is a result of an active transport mechanism mediated by the NIS protein, which is found in the basolateral membrane of thyroid follicular cells. As a result of this active transport, iodide concentration inside follicular cells of thyroid tissue is 20 to 50 times higher than in the plasma. The transport of iodide across the cell membrane is driven by the electrochemical gradient of sodium (the intracellular concentration of sodium is approximately 12 mM and extracellular concentration 140 mM). Once inside the follicular cells, the iodide diffuses to the apical membrane, where it is metabolically oxidized through the action of thyroid peroxidase to iodinium (I+) which in turn iodinates tyrosine residues of the thyroglobulin proteins in the follicle colloid. Thus, NIS is essential for the synthesis of thyroid hormones (T3 and T4).

Thyroid hormone synthesis, with the Na/I symporter seen at right.

Apart from thyroid cells NIS can also be found, although less expressed, in other tissues such as the salivary glands, the gastric mucosa, the kidney, the placenta, the ovaries and the mammary glands during pregnancy and lactation. NIS expression in the mammary glands is quite a relevant fact since the regulation of iodide absorption and its presence in the breast milk is the main source of iodine for a newborn. Note that the regulation of NIS expression in thyroid is done by the thyroid-stimulating hormone (TSH), whereas in breast is done by a combination of three molecules: prolactin, oxytocin and β-estradiol.

Inhibition

Some anions like perchlorate, pertechnetate and thiocyanate, can affect iodide capture by competitive inhibition because they can use the symporter when their concentration in plasma is high, even though they have less affinity for NIS than iodide has. Many plant cyanogenic glycosides, which are important pesticides, also act via inhibition of NIS in a large part of animal cells of herbivores and parasites and not in plant cells.

Regulation in iodine uptake

The iodine transport mechanisms are closely submitted to the regulation of NIS expression. There are two kinds of regulation on NIS expression: positive and negative regulation. Positive regulation depends on TSH, which acts by transcriptional and posttranslational mechanisms. On the other hand, negative regulation depends on the plasmatic concentrations of iodide.

Transcriptional regulation

At a transcriptional level, the TSH regulates the thyroids function through cAMP. The TSH first binds to its receptors which are joined to G proteins, and then induces the activation of the enzyme adenylate cyclase, which will raise the intracellular levels of cAMP. This can activate the CREB transcription factor (cAMP Response Element-Binding) that will bind to the CRE (cAMP Responsive Element). However, this might not occur and, instead, the increase on cAMP can be followed by PKA (Protein kinase A) activation and, as a result, the activation of the transcription factor Pax8 after suffering a phosphorylation.

These two transcription factors will influence the activity of the initiating point of transcription of the NIS gene, also known as NUE (NIS Upstream Enhancer), which is essential for the transcriptional activity of the NIS. The NUE’s activity depends on 4 relevant sites which have been identified by mutational analysis. The transcriptional factor Pax8 binds in two of this sites and its importance can be seen in the fact that Pax8 mutations lead to a decrease in the transcriptional activity of the NUE.[6] Another binding-site is the CRE, where the CREB binds, taking part in the NIS transcription.

In contrast to what has been explained above, there are growth factors such as IGF-1 and TGF-β (which is induced by the BRAF-V600E oncogene)[7] which suppress the NIS gene expression, not letting the NIS localize in the membrane.

Posttranslational regulation

The TSH can also regulate the iodide uptake at a posttranslational level, since, if it’s absent, the NIS can be resorted from the basolateral membrane of the cell in to the cytoplasm where it is no longer functional. Therefore the iodide uptake is reduced.

In addition, the NIS expression can be regulated in a negative way: high concentrations of iodide in the bloodstream will reduce considerably the levels of NIS expression, inhibiting iodide uptake and active transport of this ion. In contrast, low levels of iodide will trigger an increase in the quantity of NIS in the cell membrane, and therefore stimulate iodide’s uptake. All together this is known as the Wolf-Chaikoff effect.

NIS in thyroid diseases

The lack of iodide transport inside follicular cells tends to cause goitres. There are some mutations in the NIS DNA that cause hypothyroidism and thyroid dyshormonogenesis.

Moreover, antibodies anti-NIS have been found in thyroid autoimmune diseases. Using RT-PCR tests, it has been proved that there is no expression of NIS in cancer cells (which forms a thyroid carcinoma). Nevertheless, thanks to immunohistochemical techniques it is known that NIS is not functional in these cells, since it is mainly localized in the cytosol, and not in the basolateral membrane.

There is also a connection between the V600E mutation of the BRAF oncogene and papillary thyroid cancer that cannot concentrate iodine into its follicular cells.

Use of the NIS gene in therapies with radioiodine (131I)

The main goal for the treatment of non-thyroid carcinoma is the research of less aggressive procedures that could also provide less toxicity. One of these therapies is based on transferring NIS in cancer cells of different origin (breast, colon, prostate…) using adenoviruses or retroviruses (viral vectors). This genetic technique is called gene targeting. Once NIS is transferred in these cells, the patient is treated with radioiodine (131I), being the result a low cancer cell survival rate. Therefore, a lot is expected from these therapies.

See also

References

  1. ^ Glossary, UniProt Consortium
  2. ^ "Entrez Gene: SLC5A5 solute carrier family 5 (sodium iodide symporter), member 5". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6528.
  3. ^ Dai G, Levy O, Carrasco N (February 1996). "Cloning and characterization of the thyroid iodide transporter". Nature 379 (6564): 458–60. doi:10.1038/379458a0. PMID 8559252.
  4. ^ Smanik PA, Ryu KY, Theil KS, Mazzaferri EL, Jhiang SM (August 1997). "Expression, exon-intron organization, and chromosome mapping of the human sodium iodide symporter". Endocrinology 138 (8): 3555–8. doi:10.1210/en.138.8.3555. PMID 9231811.
  5. ^ a b Dohán O, De la Vieja A, Paroder V, Riedel C, Artani M, Reed M, Ginter CS, Carrasco N (February 2003). "The sodium/iodide Symporter (NIS): characterization, regulation, and medical significance". Endocr. Rev. 24 (1): 48–77. doi:10.1210/er.2001-0029. PMID 12588808.
  6. ^ Ohno M, Zannini M, Levy O, Carrasco N, di Lauro R (March 1999). "The paired-domain transcription factor Pax8 binds to the upstream enhancer of the rat sodium/iodide symporter gene and participates in both thyroid-specific and cyclic-AMP-dependent transcription". Mol. Cell. Biol. 19 (3): 2051–60. PMC 83998. PMID 10022892. //www.ncbi.nlm.nih.gov/pmc/articles/PMC83998/.
  7. ^ Riesco-Eizaguirre G, Rodríguez I, De la Vieja A, Costamagna E, Carrasco N, Nistal M, Santisteban P (November 2009). "The BRAFV600E oncogene induces transforming growth factor beta secretion leading to sodium iodide symporter repression and increased malignancy in thyroid cancer". Cancer Res. 69 (21): 8317–25. doi:10.1158/0008-5472.CAN-09-1248. PMID 19861538.

Further reading

External links