Sodium-iodide symporter

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

Iodine uptake
is_associated_with::Iodine uptake mediated by thyroid is_associated_with::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 is_associated_with::albumins. The rest of the iodine which remains unlinked and free in bloodstream, is removed from the body through urine (the is_associated_with::kidney is essential in the removal of iodine from extracellular space).

Iodine uptake is a result of an is_associated_with::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 is_associated_with::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 is_associated_with::thyroid peroxidase to iodinium (I+) which in turn iodinates is_associated_with::tyrosine residues of the is_associated_with::thyroglobulin proteins in the follicle colloid. Thus, NIS is essential for the synthesis of is_associated_with::thyroid hormones (T3 and T4).

Apart from thyroid cells NIS can also be found, although less expressed, in other tissues such as the is_associated_with::salivary glands, the is_associated_with::gastric mucosa, the kidney, the is_associated_with::placenta, the is_associated_with::ovaries and the is_associated_with::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 is_associated_with::thyroid-stimulating hormone (TSH), whereas in breast is done by a combination of three molecules: is_associated_with::prolactin, is_associated_with::oxytocin and β-estradiol.

Inhibition
Some anions like is_associated_with::perchlorate, is_associated_with::pertechnetate and is_associated_with::thiocyanate, can affect iodide capture by is_associated_with::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 is_associated_with::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, TSH regulates the thyroid's function through cAMP. TSH first binds to its receptors which are joined to G proteins, and then induces the activation of the enzyme is_associated_with::adenylate cyclase, which will raise the intracellular levels of cAMP. This can activate the is_associated_with::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 in cAMP can be followed by PKA (Protein kinase A) activation and, as a result, the activation of the transcription factor Pax8 after is_associated_with::phosphorylation.

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. Another binding-site is the CRE, where the CREB binds, taking part in NIS transcription.

In contrast, is_associated_with::growth factors such as is_associated_with::IGF-1 and is_associated_with::TGF-β (which is induced by the BRAF-V600E is_associated_with::oncogene) suppress NIS gene expression, not letting 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.

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

Moreover, antibodies anti-NIS have been found in thyroid is_associated_with::autoimmune diseases. Using is_associated_with::RT-PCR tests, it has been proved that there is no expression of NIS in cancer cells (which forms a is_associated_with::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 is_associated_with::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 (is_associated_with::viral vectors). This genetic technique is called is_associated_with::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.