Thesodium/iodide cotransporter, also known as thesodium/iodide symporter (NIS),[5] is aprotein that in humans is encoded by theSLC5A5gene.[6][7][8] It is a transmembraneglycoprotein with a molecular weight of 87 kDa and 13transmembrane domains, which transports twosodium cations (Na+) for eachiodide anion (I−) into the cell.[9] NIS mediated uptake of iodide intofollicular cells of thethyroid gland is the first step in the synthesis ofthyroid hormone.[9]
Iodine uptake mediated by thyroidfollicular cells from the blood plasma is the first step for the synthesis of thyroid hormones. This ingested iodine is bound to serum proteins, especially toalbumins.[10][11] The rest of the iodine which remains unlinked and free in bloodstream, is removed from the body through urine (thekidney is essential in the removal of iodine from extracellular space).
Iodine uptake is a result of anactive transport mechanism mediated by the NIS protein, which is found in thebasolateral 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.[12] The transport of iodide across the cell membrane is driven by theelectrochemical gradient of sodium (the intracellular concentration of sodium is approximately 12 mM and extracellular concentration 140 mM).[13] Once inside the follicular cells, the iodide diffuses to the apical membrane, where it is metabolically oxidized through the action ofthyroid peroxidase to iodinium (I+) which in turn iodinatestyrosine residues of thethyroglobulin proteins in the follicle colloid. Thus, NIS is essential for the synthesis ofthyroid hormones (T3 and T4).[14]
Apart from thyroid cells NIS can also be found, although less expressed, in other tissues such as thesalivary glands, thegastric mucosa, the kidney, theplacenta, theovaries and themammary glands during pregnancy and lactation.[15][16] 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 thethyroid-stimulating hormone (TSH), whereas in breast is done by a combination of three molecules:prolactin,oxytocin andβ-estradiol.[17]
Some anions likeperchlorate,pertechnetate andthiocyanate, can affect iodide capture bycompetitive 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 plantcyanogenic 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. Some evidence suggests that fluoride, such as that present in drinking water, may decrease cellular expression of the sodium/iodide symporter.[18]
A validatedin vitro radioactive iodide uptake (RAIU) assay[19] suggested that besides the traditionally known anions such as perchlorate, organic chemicals may also pose inhibition of iodide uptake via NIS.[20]
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.[21]
At a transcriptional level, TSH regulates the thyroid's function throughcAMP. TSH first binds to its receptors which are joined to G proteins, and then induces the activation of the enzymeadenylate cyclase, which will raise the intracellular levels of cAMP.[22] This can activate theCREB transcription factor (cAMP Response Element-Binding) that will bind to the CRE (cAMP Responsive Element). However, this might not occur and, instead, the increase in cAMP can be followed byPKA (Protein kinase A) activation and, as a result, the activation of the transcription factorPax8 afterphosphorylation.[23]
These two transcription factors influence the activity of NUE (NIS Upstream Enhancer), which is essential for initiating transcription of NIS. NUE's activity depends on 4 relevant sites which have been identified by mutational analysis. The transcriptional factor Pax8 binds in two of these sites. Pax8 mutations lead to a decrease in the transcriptional activity of NUE.[24] Another binding-site is the CRE, where the CREB binds, taking part in NIS transcription.
In contrast,growth factors such asIGF-1 andTGF-β (which is induced by theBRAF-V600Eoncogene)[25] suppress NIS gene expression, not letting NIS localize in the membrane.
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.[26]
Moreover, antibodies anti-NIS have been found in thyroidautoimmune diseases.[28] UsingRT-PCR tests, it has been proved that there is no expression of NIS in cancer cells (which forms athyroid 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.[29]
There is also a connection between the V600E mutation of theBRAF oncogene andpapillary thyroid cancer that cannot concentrate iodine into its follicular cells.[30]
The main goal for the treatment of non-thyroid carcinoma is the research of less aggressive procedures that could also provide less toxicity.[31] 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 calledgene targeting.[32][33] 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.[34]
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^Hallinger DR, Murr AS, Buckalew AR, Simmons SO, Stoker TE, Laws SC (April 2017). "Development of a screening approach to detect thyroid disrupting chemicals that inhibit the human sodium iodide symporter (NIS)".Toxicology in Vitro.40:66–78.doi:10.1016/j.tiv.2016.12.006.PMID27979590.
^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 Research.69 (21):8317–8325.doi:10.1158/0008-5472.CAN-09-1248.PMID19861538.S2CID11626489.
^de Souza EC, Padrón AS, Braga WM, de Andrade BM, Vaisman M, Nasciutti LE, et al. (July 2010). "MTOR downregulates iodide uptake in thyrocytes".The Journal of Endocrinology.206 (1):113–120.doi:10.1677/JOE-09-0436.PMID20392814.S2CID5333943.
^De La Vieja A, Dohan O, Levy O, Carrasco N (July 2000). "Molecular analysis of the sodium/iodide symporter: impact on thyroid and extrathyroid pathophysiology".Physiological Reviews.80 (3):1083–1105.doi:10.1152/physrev.2000.80.3.1083.PMID10893432.S2CID7565318.
^Frasca F, Nucera C, Pellegriti G, Gangemi P, Attard M, Stella M, et al. (March 2008). "BRAF(V600E) mutation and the biology of papillary thyroid cancer".Endocrine-Related Cancer.15 (1):191–205.doi:10.1677/ERC-07-0212.PMID18310287.S2CID18851007.
^Spitzweg C, O'Connor MK, Bergert ER, Tindall DJ, Young CY, Morris JC (November 2000). "Treatment of prostate cancer by radioiodine therapy after tissue-specific expression of the sodium iodide symporter".Cancer Research.60 (22):6526–6530.PMID11103823.
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