Sodium-iodide symporter

Last updated
SLC5A5
Identifiers
Aliases SLC5A5 , NIS, TDH1, solute carrier family 5 member 5
External IDs MGI: 2149330 HomoloGene: 37311 GeneCards: SLC5A5
Gene location (Human)
Ideogram human chromosome 19.svg
Chr. Chromosome 19 (human) [1]
Human chromosome 19 ideogram.svg
HSR 1996 II 3.5e.svg
Red rectangle 2x18.png
Band 19p13.11Start17,871,973 bp [1]
End17,895,174 bp [1]
RNA expression pattern
PBB GE SLC5A5 211123 at fs.png
More reference expression data
Orthologs
SpeciesHumanMouse
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: 70.88 – 70.89 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

A sodium/iodide symporter (NIS), also known as a sodium/iodide cotransporter [5] or solute carrier family 5, member 5 (SLC5A5) is a protein that in humans is encoded by the SLC5A5 gene. [6] [7] [8] 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. [9] NIS mediated uptake of iodide into follicular cells of the thyroid gland is the first step in the synthesis of thyroid hormone. [9]

Protein biological molecule consisting of chains of amino acid residues

Proteins are large biomolecules, or macromolecules, consisting of one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, responding to stimuli, providing structure to cells and organisms, and transporting molecules from one location to another. Proteins differ from one another primarily in their sequence of amino acids, which is dictated by the nucleotide sequence of their genes, and which usually results in protein folding into a specific three-dimensional structure that determines its activity.

Gene basic physical and functional unit of heredity

In biology, a gene is a sequence of nucleotides in DNA or RNA that codes for a molecule that has a function. During gene expression, the DNA is first copied into RNA. The RNA can be directly functional or be the intermediate template for a protein that performs a function. The transmission of genes to an organism's offspring is the basis of the inheritance of phenotypic trait. These genes make up different DNA sequences called genotypes. Genotypes along with environmental and developmental factors determine what the phenotypes will be. Most biological traits are under the influence of polygenes as well as gene–environment interactions. Some genetic traits are instantly visible, such as eye color or number of limbs, and some are not, such as blood type, risk for specific diseases, or the thousands of basic biochemical processes that constitute life.

Glycoprotein protein with oligosaccaride modifications

Glycoproteins are proteins which contain oligosaccharide chains (glycans) covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. Secreted extracellular proteins are often glycosylated.

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 the removal of iodine from extracellular space).

Iodine Chemical element with atomic number 53

Iodine is a chemical element with symbol I and atomic number 53. The heaviest of the stable halogens, it exists as a lustrous, purple-black non-metallic solid at standard conditions that sublimes readily to form a violet gas. The elemental form was discovered by the French chemist Bernard Courtois in 1811. It was named two years later by Joseph Louis Gay-Lussac from this property, after the Greek ἰώδης "violet-coloured".

Follicular cell

Follicular cells are cells in the thyroid gland that are responsible for the production and secretion of thyroid hormones thyroxine (T4) and triiodothyronine (T3).

Albumin family of globular proteins

The albumins are a family of globular proteins, the most common of which are the serum albumins. All the proteins of the albumin family are water-soluble, moderately soluble in concentrated salt solutions, and experience heat denaturation. Albumins are commonly found in blood plasma and differ from other blood proteins in that they are not glycosylated. Substances containing albumins, such as egg white, are called albuminoids.

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).

In cellular biology, active transport is the movement of molecules across a membrane from a region of their lower concentration to a region of their higher concentration—against the concentration gradient. Active transport requires cellular energy to achieve this movement. There are two types of active transport: primary active transport that uses ATP, and secondary active transport that uses an electrochemical gradient. An example of active transport in human physiology is the uptake of glucose in the intestines.

Electrochemical gradient gradient of electrochemical potential, usually for an ion that can move across a membrane

An electrochemical gradient is a gradient of electrochemical potential, usually for an ion that can move across a membrane. The gradient consists of two parts, the chemical gradient, or difference in solute concentration across a membrane, and the electrical gradient, or difference in charge across a membrane. When there are unequal concentrations of an ion across a permeable membrane, the ion will move across the membrane from the area of higher concentration to the area of lower concentration through simple diffusion. Ions also carry an electric charge that forms an electric potential across a membrane. If there is an unequal distribution of charges across the membrane, then the difference in electric potential generates a force that drives ion diffusion until the charges are balanced on both sides of the membrane.

Thyroid peroxidase enzyme

Thyroid peroxidase, also called thyroperoxidase (TPO) or iodide peroxidase, is an enzyme expressed mainly in the thyroid where it is secreted into colloid. Thyroid peroxidase oxidizes iodide ions to form iodine atoms for addition onto tyrosine residues on thyroglobulin for the production of thyroxine (T4) or triiodothyronine (T3), the thyroid hormones. In humans, thyroperoxidase is encoded by the TPO gene.

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

Gastric mucosa

The gastric mucosa is the mucous membrane layer of the stomach, which contains the glands and the gastric pits. In humans, it is about 1 mm thick, and its surface is smooth, soft, and velvety. It consists of simple columnar epithelium, lamina propria, and the muscularis mucosae.

Placenta organ that connects the developing foetus to the uterine wall

The placenta is a temporary organ that connects the developing fetus via the umbilical cord to the uterine wall to allow nutrient uptake, thermo-regulation, waste elimination, and gas exchange via the mother's blood supply; to fight against internal infection; and to produce hormones which support pregnancy. Placentas are a defining characteristic of placental mammals, but are also found in marsupials and some non-mammals with varying levels of development.

Thyroid-stimulating hormone (also known as thyrotropin, thyrotropic hormone, TSH, or hTSH for human TSH) is a pituitary hormone that stimulates the thyroid gland to produce thyroxine (T4), and then triiodothyronine (T3) which stimulates the metabolism of almost every tissue in the body. It is a glycoprotein hormone produced by thyrotrope cells in the anterior pituitary gland, which regulates the endocrine function of the thyroid. In 1916, Bennett M. Allen and Philip E. Smith found that the pituitary contained a thyrotropic substance.

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.

Perchlorate anion

A perchlorate is the name for a chemical compound containing the perchlorate ion, ClO−
4. The majority of perchlorates are produced commercially. Perchlorate salts are mainly used for propellants, exploiting properties as powerful oxidizing agents and to control static electricity in food packaging. Perchlorate contamination in food, water and other parts of the environment has been studied in the U.S. because of its harmful effects on human health. Perchlorate reduces thyroid hormone production in the thyroid gland.

Pertechnetate chemical compound containing pertechnetate ion

The pertechnetate ion is an oxoanion with the chemical formula TcO−
4. It is often used as a convenient water-soluble source of isotopes of the radioactive element technetium (Tc). In particular it is used to carry the 99mTc isotope which is commonly used in nuclear medicine in several nuclear scanning procedures.

Thiocyanate chemical compound

Thiocyanate is the anion [SCN]−. It is the conjugate base of thiocyanic acid. Common derivatives include the colourless salts potassium thiocyanate and sodium thiocyanate. Organic compounds containing the functional group SCN are also called thiocyanates. Mercury(II) thiocyanate was formerly used in pyrotechnics.

Using a validated in vitro radioactive iodide uptake (RAIU) assay, [10] the Besides the traditionally known anions such as perchlorate, organic chemicals may also pose inhibition of iodide uptake via NIS. [11]

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. [12] 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) [13] 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 (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

Related Research Articles

Hypothyroidism endocrine disease

Hypothyroidism, also called underactive thyroid or low thyroid, is a disorder of the endocrine system in which the thyroid gland does not produce enough thyroid hormone. It can cause a number of symptoms, such as poor ability to tolerate cold, a feeling of tiredness, constipation, depression, and weight gain. Occasionally there may be swelling of the front part of the neck due to goiter. Untreated hypothyroidism during pregnancy can lead to delays in growth and intellectual development in the baby or congenital iodine deficiency syndrome.

Iodothyronine deiodinase

Iodothyronine deiodinases (EC 1.21.99.4 and EC 1.21.99.3) are a subfamily of deiodinase enzymes important in the activation and deactivation of thyroid hormones. Thyroxine (T4), the precursor of 3,5,3'-triiodothyronine (T3) is transformed into T3 by deiodinase activity. T3, through binding a nuclear thyroid hormone receptor, influences the expression of genes in practically every vertebrate cell. Iodothyronine deiodinases are unusual in that these enzymes contain selenium, in the form of an otherwise rare amino acid selenocysteine.

Triiodothyronine chemical compound

Triiodothyronine, also known as T3, is a thyroid hormone. It affects almost every physiological process in the body, including growth and development, metabolism, body temperature, and heart rate.

Cotransporter

Cotransporters are a subcategory of membrane transport proteins (transporters) that couple the favorable movement of one molecule with its concentration gradient and unfavorable movement of another molecule against its concentration gradient. They enable cotransport and include antiporters and symporters. In general, cotransporters consist of two out of the three classes of integral membrane proteins known as transporters that move molecules and ions across biomembranes. Uniporters are also transporters but move only one type of molecule down its concentration gradient and are not classified as cotransporters.

The Wolff–Chaikoff effect, discovered by Drs. Jan Wolff and Israel Lyon Chaikoff at the University of California, is a presumed reduction in thyroid hormone levels caused by ingestion of a large amount of iodine. In 1948, Wolff and Chaikoff reported that injection of iodine in rats almost completely inhibited organification in the thyroid gland. However, recent research into the study shows that the thyroid hormone levels of the rats were not checked prior to injections.

Thyroid disease type of endocrine disease

Thyroid disease is a medical condition that affects the function of the thyroid gland. The thyroid gland is located at the front of the neck and produces thyroid hormones that travel through the blood to help regulate many other organs, meaning that it is an endocrine organ. These hormones normally act in the body to regulate energy use, infant development, and childhood development.

Thyrotropin receptor protein-coding gene in the species Homo sapiens

The thyrotropin receptor is a receptor that responds to thyroid-stimulating hormone and stimulates the production of thyroxine (T4) and triiodothyronine (T3). The TSH receptor is a member of the G protein-coupled receptor superfamily of integral membrane proteins and is coupled to the Gs protein.

PAX8 protein-coding gene in the species Homo sapiens

Paired box gene 8, also known as PAX8, is a protein which in humans is encoded by the PAX8 gene.

FOXE1 protein-coding gene in the species Homo sapiens

Forkhead box protein E1 is a protein that in humans is encoded by the FOXE1 gene.

PTTG1IP protein-coding gene in the species Homo sapiens

Pituitary tumor-transforming gene 1 protein-interacting protein (PTTG1), also known as PTTG1-binding factor (PBF), is a poorly characterised protein that in humans is encoded by the PTTG1IP gene located within the chromosomal region 21q22.3.

Thyroid hormones hormones produced by the thyroid gland

Thyroid hormones are two hormones produced and released by the thyroid gland, namely triiodothyronine (T3) and thyroxine (T4). They are tyrosine-based hormones that are primarily responsible for regulation of metabolism. T3 and T4 are partially composed of iodine. A deficiency of iodine leads to decreased production of T3 and T4, enlarges the thyroid tissue and will cause the disease known as simple goitre. The major form of thyroid hormone in the blood is thyroxine (T4), which has a longer half-life than T3. In humans, the ratio of T4 to T3 released into the blood is approximately 14:1. T4 is converted to the active T3 (three to four times more potent than T4) within cells by deiodinases (5'-iodinase). These are further processed by decarboxylation and deiodination to produce iodothyronamine (T1a) and thyronamine (T0a). All three isoforms of the deiodinases are selenium-containing enzymes, thus dietary selenium is essential for T3 production.

TSHB protein-coding gene in the species Homo sapiens

Thyroid stimulating hormone, beta also known as TSHB is a protein which in humans is encoded by the TSHB gene.

Iodotyrosine deiodinase protein-coding gene in the species Homo sapiens

Iodotyrosine deiodinase, also known as iodotyrosine dehalogenase 1, is a type of deiodinase enzyme that scavenges iodide by removing it from iodinated tyrosine residues in the thyroid gland. These iodinated tyrosines are produced during thyroid hormone biosynthesis. The iodide that is scavenged by iodotyrosine deiodinase is necessary to again synthesize the thyroid hormones. After synthesis, the thyroid hormones circulate through the body to regulate metabolic rate, protein expression, and body temperature. Iodotyrosine deiodinase is thus necessary to keep levels of both iodide and thyroid hormones in balance.

Iodine is an essential trace element in biological systems. It has the distinction of being the heaviest element commonly needed by living organisms as well as the second-heaviest known to be used by any form of life. It is a component of biochemical pathways in organisms from all biological kingdoms, suggesting its fundamental significance throughout the evolutionary history of life.

Thyroid disease in pregnancy can affect the health of the mother as well as the child before and after delivery. Thyroid disorders are prevalent in women of child-bearing age and for this reason commonly present as an intercurrent disease in pregnancy and the puerperium. Uncorrected thyroid dysfunction in pregnancy has adverse effects on fetal and maternal well-being. The deleterious effects of thyroid dysfunction can also extend beyond pregnancy and delivery to affect neurointellectual development in the early life of the child. Due to an increase in thyroxine binding globulin, an increase in placental type 3 deioidinase and the placental transfer of maternal thyroxine to the fetus, the demand for thyroid hormones is increased during pregnancy. The necessary increase in thyroid hormone production is facilitated by high human chorionic gonadotropin (hCG) concentrations, which bind the TSH receptor and stimulate the maternal thyroid to increase maternal thyroid hormone concentrations by roughly 50%. If the necessary increase in thyroid function cannot be met, this may cause a previously unnoticed (mild) thyroid disorder to worsen and become evident as gestational thyroid disease. Currently, there is not enough evidence to suggest that screening for thyroid dysfunction is beneficial, especially since treatment thyroid hormone supplementation may come with a risk of overtreatment. After women give birth, about 5% develop postpartum thyroiditis which can occur up to nine months afterwards.This is characterized by a short period of hyperthyroidism followed by a period of hypothyroidism; 20–40% remain permanently hypothyroid.

Measles virus encoding the human thyroidal sodium iodide symporter or MV-NIS is an attenuated oncolytic Edmonston (Ed) strain of measles virus.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000105641 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000000792 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:".
  4. ↑ "Mouse PubMed Reference:".
  5. ↑ Glossary, UniProt Consortium
  6. ↑ "Entrez Gene: SLC5A5 solute carrier family 5 (sodium iodide symporter), member 5".
  7. ↑ 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.
  8. ↑ 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.
  9. 1 2 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.
  10. ↑ 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. PMID   27979590.
  11. ↑ Wang J, Hallinger DR, Murr AS, Buckalew AR, Simmons SO, Laws SC, Stoker TE (April 2018). "High-Throughput Screening and Quantitative Chemical Ranking for Sodium-Iodide Symporter Inhibitors in ToxCast Phase I Chemical Library". Environmental Science & Technology. doi:10.1021/acs.est.7b06145. PMID   29611697.
  12. ↑ 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.
  13. ↑ 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

This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.