ArticlePloS one2020
Inter-species variation in monovalent anion substrate selectivity and inhibitor sensitivity in the sodium iodide symporter (NIS).
Article in PloS one, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers, 1 of them a synthesis that pooled it.
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Who cites it
13 citing papers in PubMed, 1 synthesis or guideline pooled it, 22 citations in OpenAlex.
- Interference on Iodine Uptake and Human Thyroid Function by Perchlorate-Contaminated Water and Food.Nutrients · 2020Pooled it
- The SLC-ome of membrane transport: from molecular discovery to physiology and clinical applications.Physiological reviews · 2026Review
- NitrOFF: An Engineered Fluorescent Biosensor to Illuminate Nitrate Transport in Living Cells.Angewandte Chemie (International ed. in English) · 2025Article
- Advancing in vitro assessment of iodide uptake inhibition: integrating a novel biotransformation pretreatment step.Archives of toxicology · 2025Article
- NitrOFF: An engineered fluorescent biosensor to illuminate nitrate transport in living cells.bioRxiv : the preprint server for biology · 2025Article
- Chloride channel-3 regulates sodium-iodide symporter expression and localization in the thyroids of mice on a high-iodide diet.Frontiers in nutrition · 2025Article
- Cross-species applicability of an adverse outcome pathway network for thyroid hormone system disruption.Toxicological sciences : an official journal of the Society of Toxicology · 2023Review
- A Scoping Review of Iodine and Fluoride in Pregnancy in Relation to Maternal Thyroid Function and Offspring Neurodevelopment.Advances in nutrition (Bethesda, Md.) · 2023Article
- Next-Generation Molecular Imaging of Thyroid Cancer.Cancers · 2021Review
- A brief review of reporter gene imaging in oncolytic virotherapy and gene therapy.Molecular therapy oncolytics · 2021Review
- Improved Noninvasive In Vivo Tracking of AAV-9 Gene Therapy Using the Perchlorate-Resistant Sodium Iodide Symporter from Minke Whale.Molecular therapy : the journal of the American Society of Gene Therapy · 2021Article
- Oncolytic measles virus therapy enhances tumor antigen-specific T-cell responses in patients with multiple myeloma.Leukemia · 2020Article
- Reporter Transgenes for Monitoring the Antitumor Efficacy of Recombinant Oncolytic Viruses.Acta naturaeArticle
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Authors and funding
4 authors at 2 institutions in 2 countries.
Funding
Abstract
The sodium iodide symporter (NIS) transports iodide, which is necessary for thyroid hormone production. NIS also transports other monovalent anions such as tetrafluoroborate (BF4-), pertechnetate (TcO4-), and thiocyanate (SCN-), and is competitively inhibited by perchlorate (ClO4-). However, the mechanisms of substrate selectivity and inhibitor sensitivity are poorly understood. Here, a comparative approach was taken to determine whether naturally evolved NIS proteins exhibit variability in their substrate transport properties. The NIS proteins of thirteen animal species were initially assessed, and three species from environments with differing iodide availability, freshwater species Danio rerio (zebrafish), saltwater species Balaenoptera acutorostrata scammoni (minke whale), and non-aquatic mammalian species Homo sapiens (human) were studied in detail. NIS genes from each of these species were lentivirally transduced into HeLa cells, which were then characterized using radioisotope uptake assays, 125I- competitive substrate uptake assays, and kinetic assays. Homology models of human, minke whale and zebrafish NIS were used to evaluate sequence-dependent impact on the organization of Na+ and I- binding pockets. Whereas each of the three proteins that were analyzed in detail concentrated iodide to a similar degree, their sensitivity to perchlorate inhibition varied significantly: minke whale NIS was the least impacted by perchlorate inhibition (IC50 = 4.599 μM), zebrafish NIS was highly sensitive (IC50 = 0.081 μM), and human NIS showed intermediate sensitivity (IC50 = 1.566 μM). Further studies with fifteen additional substrates and inhibitors revealed similar patterns of iodide uptake inhibition, though the degree of 125I- uptake inhibition varied with each compound. Kinetic analysis revealed whale NIS had the lowest Km-I and the highest Vmax-I. Conversely, zebrafish NIS had the highest Km and lowest Vmax. Again, human NIS was intermediate. Molecular modeling revealed a high degree of conservation in the putative ion binding pockets of NIS proteins from different species, which suggests the residues responsible for the observed differences in substrate selectivity lie elsewhere in the protein. Ongoing studies are focusing on residues in the extracellular loops of NIS as determinants of anion specificity. These data demonstrate significant transport differences between the NIS proteins of different species, which may be influenced by the unique physiological needs of each organism. Our results also identify naturally-existing NIS proteins with significant variability in substrate transport kinetics and inhibitor sensitivity, which suggest that the affinity and selectivity of NIS for certain substrates can be altered for biotechnological and clinical applications. Further examination of interspecies differences may improve understanding of the substrate transport mechanism.
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