Sodium-iodide symporter
Encyclopedia
The sodium/iodide symporter (NIS), also known as solute carrier family 5, member 5 (SLC5A5) is a protein
that in humans is encoded by the SLC5A5 gene
. 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 the cell. NIS mediated uptake of of iodide into follicular cells of the thyroid
gland is the first step in the synthesis of thyroid hormone
.
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 albumin
s. 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 reduced 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 kidney, the placenta
, the ovaries and the mammary glands during 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
.
, 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.
. 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. 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 factor
s such as IGF-1 and TGF-β (which is induced by the BRAF
-V600E oncogene
) which suppress the NIS gene expression, not letting the NIS localize in the membrane.
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.
. There are some mutations in the NIS DNA
that cause hypothyroidism
and thyroid dyshormonogenesis.
Moreover, antibodies anti-NIS have been found in thyroid autoimmune disease
s. 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.
). 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.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded by the SLC5A5 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
. The sodium/iodide symporter is a transmembrane glycoprotein
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
with a molecular weight of 87 kDa
Atomic mass unit
The unified atomic mass unit or dalton is a unit that is used for indicating mass on an atomic or molecular scale. It is defined as one twelfth of the rest mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state, and has a value of...
and 13 transmembrane domains, which transports two sodium
Sodium
Sodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...
cations (Na+) for each iodide
Iodide
An iodide ion is the ion I−. Compounds with iodine in formal oxidation state −1 are called iodides. This page is for the iodide ion and its salts. For information on organoiodides, see organohalides. In everyday life, iodide is most commonly encountered as a component of iodized salt,...
anion (I–) into the the cell. NIS mediated uptake of of iodide into follicular cells of the thyroid
Thyroid
The thyroid gland or simply, the thyroid , in vertebrate anatomy, is one of the largest endocrine glands. The thyroid gland is found in the neck, below the thyroid cartilage...
gland is the first step in the synthesis of thyroid hormone
Thyroid hormone
The thyroid hormones, thyroxine and triiodothyronine , are tyrosine-based hormones produced by the thyroid gland primarily responsible for regulation of metabolism. An important component in the synthesis of thyroid hormones is iodine. The major form of thyroid hormone in the blood is thyroxine ,...
.
Iodine uptake
IodineIodine
Iodine is a chemical element with the symbol I and atomic number 53. The name is pronounced , , or . The name is from the , meaning violet or purple, due to the color of elemental iodine vapor....
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 albumin
Albumin
Albumin refers generally to any protein that is water soluble, which is moderately soluble in concentrated salt solutions, and experiences heat denaturation. They are commonly found in blood plasma, and are unique to other blood proteins in that they are not glycosylated...
s. The rest of the iodine which remains unlinked and free in bloodstream, is removed from the body through urine (the kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
is essential in te removal of iodine from extracellular space).
Iodine uptake is a result of an active transport
Active transport
Active transport is the movement of a substance against its concentration gradient . In all cells, this is usually concerned with accumulating high concentrations of molecules that the cell needs, such as ions, glucose, and amino acids. If the process uses chemical energy, such as from adenosine...
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
Electrochemical gradient
An electrochemical gradient is a spatial variation of both electrical potential and chemical concentration across a membrane; that is, a combination of the membrane potential and the pH 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 reduced through the action of thyroid peroxidase
Thyroid peroxidase
Thyroid peroxidase or thyroperoxidase is an enzyme expressed mainly in the thyroid that liberates iodine for addition onto tyrosine residues on thyroglobulin for the production of thyroxine or triiodothyronine , thyroid hormones. In humans, thyroperoxidase is encoded by the TPO...
to iodinium (I+) which in turn iodinates tyrosine
Tyrosine
Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...
residues of the thyroglobulin
Thyroglobulin
Thyroglobulin is a 660 kDa, dimeric protein produced by and used entirely within the thyroid gland. In earlier literature, Tg was referred to as colloid....
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 kidney, the placenta
Placenta
The placenta is an organ that connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. "True" placentas are a defining characteristic of eutherian or "placental" mammals, but are also found in some snakes and...
, the ovaries and the mammary glands during 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
Thyroid-stimulating hormone
Thyrotrophin-stimulating hormone is a peptide hormone synthesized and secreted by thyrotrope cells in the anterior pituitary gland, which regulates the endocrine function of the thyroid gland.- Physiology :...
(TSH), whereas in breast is done by a combination of three molecules: prolactin
Prolactin
Prolactin also known as luteotropic hormone is a protein that in humans is encoded by the PRL gene.Prolactin is a peptide hormone discovered by Henry Friesen...
, oxytocin
Oxytocin
Oxytocin is a mammalian hormone that acts primarily as a neuromodulator in the brain.Oxytocin is best known for its roles in sexual reproduction, in particular during and after childbirth...
and β-estradiol
Estradiol
Estradiol is a sex hormone. Estradiol is abbreviated E2 as it has 2 hydroxyl groups in its molecular structure. Estrone has 1 and estriol has 3 . Estradiol is about 10 times as potent as estrone and about 80 times as potent as estriol in its estrogenic effect...
.
Inhibition
Some anions like perchloratePerchlorate
Perchlorates are the salts derived from perchloric acid . They occur both naturally and through manufacturing. They have been used as a medicine for more than 50 years to treat thyroid gland disorders. They are used extensively within the pyrotechnics industry, and ammonium perchlorate is also a...
, pertechnetate
Pertechnetate
The pertechnetate ion is an oxoanion with the chemical formula TcO4−. It is often used as a convenient water-soluble source of isotopes of the radioactive element technetium...
and thiocyanate
Thiocyanate
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...
, can affect iodide capture by competitive inhibition
Competitive inhibition
Competitive inhibition is a form of enzyme inhibition where binding of the inhibitor to the active site on the enzyme prevents binding of the substrate and vice versa.-Mechanism:...
because they can use the symporter when their concentration in plasma is high, even though they have less affinity for NIS than iodide has.
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 cAMPCyclic adenosine monophosphate
Cyclic adenosine monophosphate is a second messenger important in many biological processes...
. The TSH first binds to its receptors which are joined to G proteins, and then induces the activation of the enzyme adenylate cyclase
Adenylate cyclase
Adenylate cyclase is part of the G protein signalling cascade, which transmits chemical signals from outside the cell across the membrane to the inside of the cell ....
, which will raise the intracellular levels of cAMP. This can activate the CREB
CREB
CREB is a cellular transcription factor. It binds to certain DNA sequences called cAMP response elements , thereby increasing or decreasing the transcription of the downstream genes....
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
PAX8
Paired box gene 8, also known as PAX8, is a protein which in humans is encoded by the PAX8 gene.- Function :This gene is a member of the paired box family of transcription factors. Members of this gene family typically encode proteins which contain a paired box domain, an octapeptide, and a...
after suffering a phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
.
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. 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 factor
Growth factor
A growth factor is a naturally occurring substance capable of stimulating cellular growth, proliferation and cellular differentiation. Usually it is a protein or a steroid hormone. Growth factors are important for regulating a variety of cellular processes....
s such as IGF-1 and TGF-β (which is induced by the BRAF
BRAF (gene)
Serine/threonine-protein kinase B-Raf or simply B-Raf, also known as proto-oncogene B-Raf or v-Raf murine sarcoma viral oncogene homolog B1, is a protein that in humans is encoded by the BRAF gene...
-V600E oncogene
Oncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, they are often mutated or expressed at high levels.An oncogene is a gene found in the chromosomes of tumor cells whose activation is associated with the initial and continuing conversion of normal cells into cancer...
) 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 goitresGoitre
A goitre or goiter , is a swelling in the thyroid gland, which can lead to a swelling of the neck or larynx...
. There are some mutations in the NIS DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
that cause hypothyroidism
Hypothyroidism
Hypothyroidism is a condition in which the thyroid gland does not make enough thyroid hormone.Iodine deficiency is the most common cause of hypothyroidism worldwide but it can be caused by other causes such as several conditions of the thyroid gland or, less commonly, the pituitary gland or...
and thyroid dyshormonogenesis.
Moreover, antibodies anti-NIS have been found in thyroid autoimmune disease
Autoimmune disease
Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body. In other words, the body actually attacks its own cells. The immune system mistakes some part of the body as a pathogen and attacks it. This may be restricted to...
s. 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
BRAF (gene)
Serine/threonine-protein kinase B-Raf or simply B-Raf, also known as proto-oncogene B-Raf or v-Raf murine sarcoma viral oncogene homolog B1, is a protein that in humans is encoded by the BRAF gene...
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 vectorsViral vector
Viral vectors are a tool commonly used by molecular biologists to deliver genetic material into cells. This process can be performed inside a living organism or in cell culture . Viruses have evolved specialized molecular mechanisms to efficiently transport their genomes inside the cells they infect...
). This genetic technique is called gene targeting
Gene targeting
Gene targeting is a genetic technique that uses homologous recombination to change an endogenous gene. The method can be used to delete a gene, remove exons, add a gene, and introduce point mutations. Gene targeting can be permanent or conditional...
. 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.