Human Transporters

NISNew

NIS (Na+ / I- symporter)

Aliases: TDH1, Na+ / I- cotransporter

Gene name: Solute carrier family member 5 (SLC5A5)

 

Summary

NIS uses the Na+ gradient generated by the Na+/K+-ATPase to mediate the active uptake of I- in the thyroid and some extrathyroidal tissues. In the thyroid, it plays a key role in the biosynthesis of the iodide-containing thyroid hormones (THs), which are crucial for normal development and metabolism. Apart from its well-known I- transport activity, NIS also mediates the translocation of other anions, including the environmental pollutants NO3-, SCN- and ClO4-. These competitive inhibitors block the thyroidal uptake of I-, thus perturb the TH signaling system and the TH-regulated functions. The Organization for Economic Co-operation and Development (OECD) refers to the NIS transporter as a potential target of environmental chemicals that influence thyroid hormone synthesis.

Localization

Although NIS function is mainly associated with the thyroid, functional NIS is found in other tissues as well. It is present in the lacrimal sac, nasolacrimal duct, salivary glands, choroid plexus, stomach, intestine, lactating breast, kidney, placenta and ovary. NIS is expressed on the basolateral surface of epithelial cells of the salivary gland, thyroid, gestational breast, and stomach. By contrast, placental cytotrophoblasts, as well as intestinal and kidney epithelial cells show apical localization [1,2,3].

Function, physiology, and clinically significant polymorphism

NIS is an intrinsic membrane glycoprotein with 13 transmembrane domains [4]. Its role is to catalyze the active accumulation of iodide in the thyroid gland and nonthyroidal tissues. The active accumulation of I- is electrogenic, with a 2 Na+: 1 I- stoichiometry. The driving force of this process is the Na+ gradient generated by the Na+/K+-ATPase [5]. The low affinity (Kd=224 mM) of NIS for I- increases 10-fold when Na+ is already bound [6]. Some Na+-dependent transporters accept monovalent cations other than Na+, whereas NIS-mediated transport has been shown to be highly specific to Na+. It cannot be driven by H+ and shows very low activity (10-20%) in the presence of Li+ [2].

In the thyroid, NIS accumulates I- in the thyrocytes to concentrations 20-40 fold higher than serum levels [7]. Inside the thyroid follicles, I- is oxidized by thyroid peroxidase (TPO), and elementary iodine becomes incorporated into thyroglobulin (TG) by spontaneously reacting with its tyrosyl residues. TG is a highly glycosylated homodimer stored in the colloid of the thyroid and is the precursor of the thyroid hormones triiodothyronine (T3) and tetraiodothyronine (T4), possessing 3 and 4 iodine atoms, respectively. These hormones are released from the colloid into the blood in response to stimulation by the thyroid-stimulating hormone (TSH) [2,5]. THs are important regulators of intermediary metabolism in the entire organism. T3 and T4 are essential for the normal development of the central nervous system, skeletal muscle and lungs [8].

The primary regulator of thyroidal NIS is TSH at both transcriptional and posttranscriptional levels. TSH positively regulates NIS mRNA and protein expression and therefore iodide accumulation. Moreover, when TSH is present, NIS is localized in the basolateral membrane of thyrocytes. In the absence of TSH, the half-life of NIS decreases and it translocates from the membrane to intracellular compartments. Another transcriptional regulator is I-, with its high doses reducing NIS mRNA and protein levels [9].

In addition to I-, NIS also mediates the transport of other anions. Pseudohalides such as thiocyanate (SCN-), hexafluorophosphate (PF6), and monovalent anions such as nitrate (NO3-), chlorate (ClO3-), perchlorate (ClO4-), and perrhenate (ReO4-) are also substrates and block iodide translocation by competition for the iodide binding and transport site of NIS [6,10]. Of these competitive inhibitors NO3-, SCN-, and  ClO4- are of particular dietary and/or environmental importance (see Clinical significance) [7]. To a lower extent Br-, BF4-, IO4- and BrO3- are also transported. NIS also transports different radioisotopes such as pertechnetate (TcO4-) and astatine (At-) [2,11].

The affinity of the transporter for ReO4- and ClO4- is 10-fold higher, for SCN- is similar, and for ClO3- and NO3- is 10- to 20-fold lower than for I- [6,12,13]. A remarkable property of NIS is that it transports different substrates with different stoichiometries. It transports I-, SCN-, ClO3- with an electrogenic stoichiometry of 2 Na+:1 anion. In contrast, ReO4- and ClO4- is transported with an electroneutral stoichiometry of 1 Na+:1 anion [14].

Dysidenin, metiram, 5-(N,N-hexamethylene)amiloride (HMA) and econazole are known inhibitors of NIS-mediated iodide transport [11]. Ten chemicals specifically designed to inhibit NIS activity were named iodide transporter blockers (ITB-1 to ITB-10) [15].  Ouabain and other cardiotonic glycosides are Na+/K+-ATPase inhibitors and therefore strongly decrease the iodide transport in thyroid cells. Harmaline inhibits the I- transport by competing for the Na+ binding site of NIS. However, the inhibition is not specific as it targets other Na+-dependent transporters by the same mechanism. It has been shown that ITB-3 to -9 and ClO4- inhibit the I- transport immediately, in contrast to ITB-1, ITB-2, ITB-10, dysidenin and ouabain, which show time-dependent, delayed inhibition [6]. The strongest inhibitors were ouabain, ITB-10 , ITB-9 and metiram [15].

Biallelic mutations in the NIS coding SLC5A5 gene cause an autosomal recessive disorder, congenital iodide transport defect (ITD). Up to date, eighteen different loss-of-function mutations have been identified in patients with ITD [16,17]. In the absence of functional NIS, I- cannot enter the thyroid epithelial cells. This results in decreased THs synthesis and elevated serum TSH level, which cause morphological and biochemical changes in the thyroid leading to the development of goiter [18].

Clinical significance

Endocrine disrupting chemicals (EDCs) in the environment can cause adverse health effects, especially when the exposure happens during such critical periods as reproduction and development. Various xenobiotics can perturb the TH signaling system and therefore the TH-regulated functions [19,20]. Thyroid-disruptive chemicals target TH synthesis, secretion, transport and metabolism [19]. Such environmental NIS substrates are NO3-, SCN- and ClO4-. The main exposure to SCN- is dietary and environmental. In dietary consumption, it originates from the metabolism of plant-derived thioglucosides, but the most important source of exposure is cigarette smoke, through the hepatic detoxification of cyanide. NO3- is the end-product of nitric oxide metabolism, a natural vegetable component, and a food additive. The usage of nitrate containing fertilizers and the industrial emission of nitrogen containing compounds have led to contamination of drinking water and increased consumption. ClO3- and ClO4- are also products of industrial pollution and contaminants of drinking water [12,21]. These substrates are competing for the I- binding and transport site of NIS, and thus block its transport [6], with serious consequences on both thyroidal and extrathyroidal tissues. In the thyroid gland, despite adequate I- uptake, NIS blockers can cause development of goiter and associated iodine deficiency disorders (IDDs). In the lactating breast, NIS mediates the transport of I- into the milk, which is the only supply of this essential anion for the baby. ClO4- transported by NIS in the lactating breast not only decreases milk I- levels by competitively inhibiting I- export but also interferes with the thyroidal uptake of I- in the newborn [8].  This effect can perturb the normal mental and physical development of the child.

The uptake of radioactive I- by NIS is widely used in medical diagnosis and therapy. The uptake of 131I- was first used to treat hyperthyroidism, and thyroid cancer after thyroidectomy [22,23]. By using different gene delivery systems for NIS transgene expression, it can be used for gene therapy. NIS-based gene therapy enables the radiotreatment of nonthyroidal tumors by the uptake of therapeutic radionuclides. At the same time, the NIS transgene can be also used as a reporter gene for noninvasive imaging techniques, such as 123I- scintigraphy and 124I- PET imaging  [24,25,26]. Monitoring I- uptake can also assist the differential diagnosis of thyroid nodules. Benign thyroid nodules usually concentrate I- to a similar or greater extent compared with the healthy tissue, whereas most thyroid cancers display reduced accumulation [18].

Regulatory requirements

The new scoping document “In vitro and ex vivo assays for the identification of modulators of thyroid hormone signaling” published by The Organization for Economic Co-operation and Development (OECD) refers to the NIS transporter as a potential target of environmental chemicals that influence thyroid hormone synthesis [27]. Nevertheless, testing the interaction of NIS with NCEs is not recommended by current FDA or EMA guidelines.

Summary information for NIS (table)

Location

Endogenous substrates

In vitro substrates used experimentally

Substrate drugs

Inhibitors

lacrimal sac, nasolacrimal duct, salivary glands, choroid plexus, stomach, intestine, lactating breast, kidney, placenta, ovary

iodide

thiocyanate, hexafluorophosphate, chlorate, tetrafluoroborate, nitrate

none

perrhenate, perchlorate, ITB 1-10, dysidenin, econazole, metiram, HMA, mancozeb, DBP, cypermethrin, triclocarban, deltamethrin, indomethacin, TCS, thiram, triallate, ziram

 

References

1.          Ravera S, Reyna-Neyra A, Ferrandino G, Amzel LM, Carrasco N. The Sodium/Iodide Symporter (NIS): Molecular Physiology and Preclinical and Clinical Applications. Annu Rev Physiol. 2017;79(1):261-289. doi:10.1146/annurev-physiol-022516-034125

2.          Portulano C, Paroder-Belenitsky M, Carrasco N. The Na+/I- Symporter (NIS): Mechanism and medical impact. Endocr Rev. 2014;35(1):106-149. doi:10.1210/er.2012-1036

3.          De La Vieja A, Santisteban P. Role of iodide metabolism in physiology and cancer. Endocr Relat Cancer. 2018;25(4):R225-R245. doi:10.1530/ERC-17-0515

4.          Levy O, De La Vieja A, Carrasco N. The Na+/i- symporter (NIS): Recent advances. J Bioenerg Biomembr. 1998;30(2):195-206. doi:10.1023/A:1020577426732

5.          Carrasco N. Iodide transport in the thyroid gland. BBA - Rev Biomembr. 1993;1154(1):65-82. doi:10.1016/0304-4157(93)90017-I

6.          Lecat-Guillet N, Merer G, Lopez R, Pourcher T, Rousseau B, Ambroise Y. Small-molecule inhibitors of sodium iodide symporter function. ChemBioChem. 2008;9(6):889-895. doi:10.1002/cbic.200700682

7.          Tonacchera M, Pinchera A, Dimida A, et al. Radioactive Iodide Uptake by the Human Sodium Iodide Symporter. Thyroid. 2004;14(12):1012-1019.

8.          Dohán O, Portulano C, Basquin C, Reyna-Neyra A, Amzel LM, Carrasco N. The Na+/I- symporter (NIS) mediates electroneutral active transport of the environmental pollutant perchlorate. Proc Natl Acad Sci U S A. 2007;104(51):20250-20255. doi:10.1073/pnas.0707207104

9.          Bizhanova A, Kopp P. Minireview: The sodium-iodide symporter NIS and pendrin in iodide homeostasis of the thyroid. Endocrinology. 2009;150(3):1084-1090. doi:10.1210/en.2008-1437

10.       Clewell RA, Merrill EA, Narayanan L, Gearhart JM, Robinson PJ. Evidence for Competitive Inhibition of Iodide Uptake by Perchlorate and Translocation of Perchlorate into the Thyroid. Int J Toxicol. 2004;23(1):17-23. doi:10.1080/10915810490275044

11.       Darrouzet E, Lindenthal S, Marcellin D, Pellequer JL, Pourcher T. The sodium/iodide symporter: State of the art of its molecular characterization. Biochim Biophys Acta - Biomembr. 2014;1838(1 PARTB):244-253. doi:10.1016/j.bbamem.2013.08.013

12.       Di Bernardo J, Iosco C, Rhoden KJ. Intracellular anion fluorescence assay for sodium/iodide symporter substrates. Anal Biochem. 2011;415(1):32-38. doi:10.1016/j.ab.2011.04.017

13.       Van Sande J, Massart C, Beauwens R, et al. Anion selectivity by the sodium iodide symporter. Endocrinology. 2003;144(1):247-252. doi:10.1210/en.2002-220744

14.       Paroder-Belenitsky M, Maestas MJ, Dohán O, et al. Mechanism of anion selectivity and stoichiometry of the Na +/I - symporter (NIS). Proc Natl Acad Sci U S A. 2011;108(44):17933-17938. doi:10.1073/pnas.1108278108

15.       Dong H, Atlas E, Wade MG. Development of a non-radioactive screening assay to detect chemicals disrupting the human sodium iodide symporter activity. Toxicol Vitr. 2019;57(February):39-47. doi:10.1016/j.tiv.2019.01.021

16.       Martín M, Nicola JP. Iodide Transport Defect : Recent Advances and Future Perspectives Keywords The Significance of Dietary Iodide Congenital Hypothyroidism Sodium Iodide Symporter ( NIS ). MedPub Journals. 2016:80-85.

17.       Martín M, Bernal Barquero CE, Geysels RC, et al. Novel Sodium/Iodide Symporter Compound Heterozygous Pathogenic Variants Causing Dyshormonogenic Congenital Hypothyroidism. Thyroid. 2019;29(7):1023-1026. doi:10.1089/thy.2019.0046

18.       De La Vieja A, Dohan O, Levy O, Carrasco N. Molecular analysis of the sodium/ iodide symporter: Impact on thyroid and extrathyroid pathophysiology. Physiol Rev. 2000;80(3):1083-1105. doi:10.1152/physrev.2000.80.3.1083

19.       Wang J, Hallinger DR, Murr AS, et al. High-Throughput Screening and Quantitative Chemical Ranking for Sodium-Iodide Symporter Inhibitors in ToxCast Phase i Chemical Library. Environ Sci Technol. 2018;52(9):5417-5426. doi:10.1021/acs.est.7b06145

20.       Boas M, Feldt-Rasmussen U, Main KM. Thyroid effects of endocrine disrupting chemicals. Mol Cell Endocrinol. 2012;355(2):240-248. doi:10.1016/j.mce.2011.09.005

21.       Willemin ME, Lumen A. Thiocyanate: a review and evaluation of the kinetics and the modes of action for thyroid hormone perturbations. Crit Rev Toxicol. 2017;47(7):537-563. doi:10.1080/10408444.2017.1281590

22.       Hertz S, Roberts A, Evans RD. Radioactive Iodine as an Indicator in the Study of Thyroid Physiology. Proc Soc Exp Biol Med. 1938;38(4):510-513. doi:10.3181/00379727-38-9915P

23.       Seidlin SM, Marinelli LD, Oshry E. Radioactive iodine therapy: effect on functioning metastases of adenocarcinoma of the thyroid. CA Cancer J Clin. 1990;40(5):299-317. doi:10.3322/canjclin.40.5.299

24.       Spitzweg C, O’Connor MK, Bergert ER, Tindall DJ, Young CYF, Morris JC. Treatment of prostate cancer by radioiodine therapy after tissue-specific expression of the sodium iodide symporter. Cancer Res. 2000;60(22):6526-6530.

25.       Schmohl KA, Gupta A, Grünwald GK, et al. Imaging and targeted therapy of pancreatic ductal adenocarcinoma using the theranostic sodium iodide symporter (NIS) gene. Oncotarget. 2017;8(20):33393-33404. doi:10.18632/oncotarget.16499

26.       Klutz K, Willhauck MJ, Wunderlich N, et al. Sodium iodide symporter (NIS)-mediated radionuclide ( 131I, 188Re) therapy of liver cancer after transcriptionally targeted intratumoral in vivo NIS gene delivery. Hum Gene Ther. 2011;22(11):1403-1412. doi:10.1089/hum.2010.158

27.       OECD. In Vitro & Ex Vivo Assays for Identification of Modulators of Thyroid Hormone Signalling. 2013:76.

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