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SLC5A5
Identifiers
Aliases	SLC5A5, NIS, TDH1, solute carrier family 5 member 5
External IDs	OMIM: 601843; MGI: 2149330; HomoloGene: 37311; GeneCards: SLC5A5; OMA:SLC5A5 - orthologs
Gene location (Human) Chr. Chromosome 19 (human) Band 19p13.11 Start 17,871,945 bp End 17,895,174 bp
Gene location (Mouse) Chr. Chromosome 8 (mouse) Band 8|8 B3.3 Start 71,335,533 bp End 71,345,401 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in gastric mucosa deltoid muscle mucosa of ileum tibialis anterior muscle body of stomach testicle pharynx gonad salivary gland tonsil Top expressed in epithelium of stomach lumbar spinal ganglion facial motor nucleus submandibular gland pyloric antrum supraoptic nucleus gastrula Epithelium of choroid plexus embryo primary visual cortex More reference expression data BioGPS More reference expression data
Gene ontology Molecular function transporter activity symporter activity iodide transmembrane transporter activity sodium:iodide symporter activity transmembrane transporter activity Cellular component integral component of membrane extracellular vesicle membrane extracellular exosome nucleus plasma membrane Biological process sodium ion transmembrane transport sodium ion transport ion transport anion transmembrane transport cellular response to gonadotropin stimulus cellular response to cAMP transmembrane transport thyroid hormone generation iodide transport transport Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 6528 114479 Ensembl ENSG00000105641 ENSMUSG00000000792 UniProt Q92911 Q99PN0 RefSeq (mRNA) NM_000453 NM_053248 RefSeq (protein) NP_000444 NP_444478 Location (UCSC) Chr 19: 17.87 – 17.9 Mb Chr 8: 71.34 – 71.35 Mb PubMed search
Wikidata
View/Edit Human View/Edit Mouse

The sodium/iodide cotransporter, also known as the sodium/iodide symporter (NIS), is a protein that in humans is encoded by the SLC5A5 gene. It 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. NIS mediated uptake of iodide into follicular cells of the thyroid gland is the first step in the synthesis of thyroid hormone.

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. The rest of the iodine which remains unlinked and free in bloodstream, is removed from the body through urine (the kidney is essential in the 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).

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 by Environmental Chemicals

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. Some evidence suggests that fluoride, such as that present in drinking water, may decrease cellular expression of the sodium/iodide symporter.

Using a validated in vitro radioactive iodide uptake (RAIU) assay, the Besides the traditionally known anions such as perchlorate, organic chemicals may also pose inhibition of iodide uptake via NIS.

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 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 in cAMP can be followed by PKA (Protein kinase A) activation and, as a result, the activation of the transcription factor Pax8 after 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, growth factors such as IGF-1 and TGF-β (which is induced by the BRAF-V600E 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.

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 with radioiodine (I)

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 (I), being the result a low cancer cell survival rate. Therefore, a lot is expected from these therapies.

See also

• Symporter
• Solute carrier family

References

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Further reading

• Santisteban P. "Mecanismos Moleculares Implicados en la Función Tiroidea: Control de Procesos Fisiológicos y Alteraciones Pathológicas" [Molecular Mechanisms Involved in Thyroid Function: Physiological Process Control and Pathological Alterations] (PDF) (in Spanish). Universidad de Vigo. Archived from the original (PDF) on 2012-04-06. Retrieved 2011-11-18.
• Carlos D, Rafael Y, eds. (2007). "Fisiología del tiroides" [Thyroid Physiology]. Tiroides [Thyroid] (in Spanish) (2nd ed.). Aravaca (Madrid): McGRAW-HILL – INTERAMERICANA. pp. 1–30.
• Jameson JL, Weetman AP (2010). "Disorders of the Thyroid Gland". In Jameson JL (ed.). Harrison's Endocrinology. McGraw-Hill Medical. pp. 62–98. ISBN 978-0-07-174144-6.
• Fukushima K, Kaneko CR, Fuchs AF (December 1992). "The neuronal substrate of integration in the oculomotor system". Progress in Neurobiology. 39 (6): 609–639. doi:10.1016/0301-0082(92)90016-8. PMID 1410443. S2CID 40209167.
• 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. PMID 10893432. S2CID 7565318.
• Dohán O, De la Vieja A, Paroder V, Riedel C, Artani M, Reed M, et al. (February 2003). "The sodium/iodide Symporter (NIS): characterization, regulation, and medical significance". Endocrine Reviews. 24 (1): 48–77. doi:10.1210/er.2001-0029. PMID 12588808.
• Kogai T, Taki K, Brent GA (September 2006). "Enhancement of sodium/iodide symporter expression in thyroid and breast cancer". Endocrine-Related Cancer. 13 (3): 797–826. doi:10.1677/erc.1.01143. PMID 16954431.
• Riesco-Eizaguirre G, Santisteban P (October 2006). "A perspective view of sodium iodide symporter research and its clinical implications". European Journal of Endocrinology. 155 (4): 495–512. doi:10.1530/eje.1.02257. PMID 16990649.
• Libert F, Passage E, Lefort A, Vassart G, Mattei MG (1991). "Localization of human thyrotropin receptor gene to chromosome region 14q3 by in situ hybridization". Cytogenetics and Cell Genetics. 54 (1–2): 82–83. doi:10.1159/000132964. PMID 2249482.
• Albero R, Cerdan A, Sanchez Franco F (December 1987). "Congenital hypothyroidism from complete iodide transport defect: long-term evolution with iodide treatment". Postgraduate Medical Journal. 63 (746): 1043–1047. doi:10.1136/pgmj.63.746.1043. PMC 2428598. PMID 3451231.
• Couch RM, Dean HJ, Winter JS (June 1985). "Congenital hypothyroidism caused by defective iodide transport". The Journal of Pediatrics. 106 (6): 950–953. doi:10.1016/S0022-3476(85)80249-3. PMID 3998954.
• Smanik PA, Liu Q, Furminger TL, Ryu K, Xing S, Mazzaferri EL, Jhiang SM (September 1996). "Cloning of the human sodium lodide symporter". Biochemical and Biophysical Research Communications. 226 (2): 339–345. doi:10.1006/bbrc.1996.1358. PMID 8806637.
• Fujiwara H, Tatsumi K, Miki K, Harada T, Miyai K, Takai S, Amino N (June 1997). "Congenital hypothyroidism caused by a mutation in the Na+/I- symporter". Nature Genetics. 16 (2): 124–125. doi:10.1038/ng0697-124. PMID 9171822. S2CID 20911347.
• 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): 3555–3558. doi:10.1210/endo.138.8.5262. PMID 9231811.
• Saito T, Endo T, Kawaguchi A, Ikeda M, Nakazato M, Kogai T, Onaya T (October 1997). "Increased expression of the Na+/I- symporter in cultured human thyroid cells exposed to thyrotropin and in Graves' thyroid tissue". The Journal of Clinical Endocrinology and Metabolism. 82 (10): 3331–3336. doi:10.1210/jcem.82.10.4269. PMID 9329364.
• Pohlenz J, Medeiros-Neto G, Gross JL, Silveiro SP, Knobel M, Refetoff S (November 1997). "Hypothyroidism in a Brazilian kindred due to iodide trapping defect caused by a homozygous mutation in the sodium/iodide symporter gene". Biochemical and Biophysical Research Communications. 240 (2): 488–491. doi:10.1006/bbrc.1997.7594. PMID 9388506.
• Matsuda A, Kosugi S (December 1997). "A homozygous missense mutation of the sodium/iodide symporter gene causing iodide transport defect". The Journal of Clinical Endocrinology and Metabolism. 82 (12): 3966–3971. doi:10.1210/jcem.82.12.4425. PMID 9398697.
• Pohlenz J, Rosenthal IM, Weiss RE, Jhiang SM, Burant C, Refetoff S (March 1998). "Congenital hypothyroidism due to mutations in the sodium/iodide symporter. Identification of a nonsense mutation producing a downstream cryptic 3' splice site". The Journal of Clinical Investigation. 101 (5): 1028–1035. doi:10.1172/JCI1504. PMC 508654. PMID 9486973.
• Venkataraman GM, Yatin M, Ain KB (January 1998). "Cloning of the human sodium-iodide symporter promoter and characterization in a differentiated human thyroid cell line, KAT-50". Thyroid. 8 (1): 63–69. doi:10.1089/thy.1998.8.63. PMID 9492156.
• Levy O, Ginter CS, De la Vieja A, Levy D, Carrasco N (June 1998). "Identification of a structural requirement for thyroid Na+/I- symporter (NIS) function from analysis of a mutation that causes human congenital hypothyroidism". FEBS Letters. 429 (1): 36–40. doi:10.1016/S0014-5793(98)00522-5. PMID 9657379. S2CID 34156341.
• Fujiwara H, Tatsumi K, Miki K, Harada T, Okada S, Nose O, et al. (August 1998). "Recurrent T354P mutation of the Na+/I- symporter in patients with iodide transport defect". The Journal of Clinical Endocrinology and Metabolism. 83 (8): 2940–2943. doi:10.1210/jcem.83.8.5029. PMID 9709973.
• Kosugi S, Inoue S, Matsuda A, Jhiang SM (September 1998). "Novel, missense and loss-of-function mutations in the sodium/iodide symporter gene causing iodide transport defect in three Japanese patients". The Journal of Clinical Endocrinology and Metabolism. 83 (9): 3373–3376. doi:10.1210/jcem.83.9.5245. PMID 9745458.

External links

• sodium-iodide+symporter at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Bowen R (2003-03-10). "The Sodium-Iodide Symporter". Pathophysiology of the Endocrine System. Colorado State University. Archived from the original on 1999-10-02. Retrieved 2008-08-11.

• Genes on human chromosome 19
• Solute carrier family
• Thyroid