The Sodium/Iodide Symporter (NIS): Molecular Physiology and Preclinical and Clinical Applications

Abstract

Active iodide (I^-) transport in both the thyroid and some extrathyroidal tissues is mediated by the Na⁺/I^- symporter (NIS). In the thyroid, NIS-mediated I^- uptake plays a pivotal role in thyroid hormone (TH) biosynthesis. THs are key during embryonic and postembryonic development and critical for cell metabolism at all stages of life. The molecular characterization of NIS in 1996 and the use of radioactive I^- isotopes have led to significant advances in the diagnosis and treatment of thyroid cancer and provide the molecular basis for studies aimed at extending the use of radioiodide treatment in extrathyroidal malignancies. This review focuses on the most recent findings on I^- homeostasis and I^- transport deficiency-causing NIS mutations, as well as current knowledge of the structure/function properties of NIS and NIS regulatory mechanisms. We also discuss employing NIS as a reporter gene using viral vectors and stem cells in imaging, diagnostic, and therapeutic procedures.

Keywords: NIS mutations; gene transfer studies; imaging and radioiodide therapy; sodium/iodide symporter; structure/function; thyroid hormones.

Figure 1

Schematic representation of TH biogenesis. (a) Experimentally tested NIS secondary structure model (upper left). TMSs are represented by cylinders of different colors, which match those used in the depiction of the current NIS homology model (lower left) based on the crystal structure of vSGLT. Blue lines represent extracellular and intracellular segments, and branches represent N-linked glycosylation sites (N225, 489, and 502). NIS mutations identified in patients with ITD and studied at the molecular level by investigating the effects of different amino acid substitutions at the relevant positions are named using the single-letter amino acid code. Δ indicates deletions. (b) Schematic representation of thyroid hormone biogenesis: NIS (blue), TG (green), TPO (red), DUOX2 (yellow), and KCNQ1-KCNE2 potassium channel (yellow and brown at the basolateral surface structures). Abbreviations: DEHAL-1, dehalogenase 1; DIT, 3,5-di-iodotyrosine; DUOX2, dual oxidase 2; ITD, I⁻ transport defect; MIT, 3-mono-iodotyrosine; NIS, Na⁺/I⁻ symporter; TG, thyroglobulin; TH, thyroid hormone; TMS, transmembrane segment; TPO, thyroid peroxidase; TSH, thyroid-stimulating hormone; TSHR, TSH receptor; vSGLT, Vibrio parahaemolyticus Na⁺/galactose transporter.

Figure 2

NIS expression in the thyroid and extrathyroidal tissues. NIS expression in tissues that actively transport I⁻ was detected by IHC using affinity-purified anti-NIS antibodies. Epithelial cells from (1) salivary gland, (2) Graves’ thyroid, (3) gestational breast, and (4) stomach show basolateral expression; by contrast, (5) intestine epithelial cells show apical localization. Images shown at magnifications of × 40 (3), ×60 (2, 5), and ×100 (1, 4). Images 2 and 4 are adapted from Reference , and image 5 is adapted from Reference . Abbreviations: IHC, immunohistochemistry; NIS, Na⁺/I⁻ symporter.

Figure 3

Na⁺/I⁻ symporter (NIS)-mediated [¹⁸F]-tetrafluoroborate biodistribution in macaques. Maximum-intensity projection positron emission tomography images of [¹⁸F]-tetrafluoroborate at different time points following intravenous injection of the isotope. Adapted from Reference under the terms of the Creative Commons Attribution 4.0 International License, http://creativecommons.org/licenses/by/4.0.

Figure 4

Summary of properties of ITD-causing NIS mutations characterized at the molecular level. ❶ Residue interaction in the three-dimensional NIS homology model; ❷ amino acid substitution or deletion, country of origin of ITD patient, and mutation location in NIS; ❸ amino acid function at the relevant position; and ❹ molecular requirement at the position. Abbreviations: ITD, I⁻ transport defect; NIS, Na⁺/I⁻ symporter; PM, plasma membrane; TMS, transmembrane segment.

Figure 5

SLC5 family alignment. Residues corresponding to the NIS positions found mutated in ITD patients that have been characterized at the molecular level are highlighted in red. Rectangles represent NIS TMSs (colors are the same as in Figure 1a); lines represent intracellular loops in NIS. Abbreviations: ITD, I⁻ transport defect; NIS, Na⁺/I⁻ symporter; TMS, transmembrane segment.

Figure 6

NIS expression as imaged by ¹²³I⁻ uptake in one of the study patients. The ¹²³I⁻ SPECT/CT scan was negative at baseline (a) but became positive on day 8 of cycle 1 (b). Reprinted with permission from Reference . Copyright 2015, American Association for Cancer Research. Abbreviations: CT, computed tomography; NIS, Na⁺/I⁻ symporter; SPECT, single-photon emission computed tomography.