The Na+/I− Symporter (NIS): Mechanism and Medical Impact

Abstract

The Na(+)/I(-) symporter (NIS) is the plasma membrane glycoprotein that mediates active I(-) transport in the thyroid and other tissues, such as salivary glands, stomach, lactating breast, and small intestine. In the thyroid, NIS-mediated I(-) uptake plays a key role as the first step in the biosynthesis of the thyroid hormones, of which iodine is an essential constituent. These hormones are crucial for the development of the central nervous system and the lungs in the fetus and the newborn and for intermediary metabolism at all ages. Since the cloning of NIS in 1996, NIS research has become a major field of inquiry, with considerable impact on many basic and translational areas. In this article, we review the most recent findings on NIS, I(-) homeostasis, and related topics and place them in historical context. Among many other issues, we discuss the current outlook on iodide deficiency disorders, the present stage of understanding of the structure/function properties of NIS, information gleaned from the characterization of I(-) transport deficiency-causing NIS mutations, insights derived from the newly reported crystal structures of prokaryotic transporters and 3-dimensional homology modeling, and the novel discovery that NIS transports different substrates with different stoichiometries. A review of NIS regulatory mechanisms is provided, including a newly discovered one involving a K(+) channel that is required for NIS function in the thyroid. We also cover current and potential clinical applications of NIS, such as its central role in the treatment of thyroid cancer, its promising use as a reporter gene in imaging and diagnostic procedures, and the latest studies on NIS gene transfer aimed at extending radioiodide treatment to extrathyroidal cancers, including those involving specially engineered NIS molecules.

ANIMAL MODELS OF DISEASE: Feline hyperthyroidism: an animal model for toxic nodular goiter

“…Radioactive iodine, such as stable iodine, is trapped and concentrated within thyroid follicular cells by the sodium/iodine symporter (i.e. the iodine pump; Portulano et al 2014). Once within the cell, iodine is oxidized to iodide as it passes though the thyroid follicular cell to the lumen of the thyroid follicle.…”

Na + coordination at the Na2 site of the Na + /I − symporter

“…Besides the thyroid, NIS mediates active I − transport in several other tissues, including the lactating breast (7), salivary glands (7,8), stomach (9), and small intestine (10,11). The function of NIS appears to be an evolutionary adaptation to the scant amount of I − in the environment (12,13).…”

Risk of Breast Cancer in Patients with Thyroid Cancer Receiving or Not Receiving 131I Treatment: A Nationwide Population-Based Cohort Study

“…The NIS is also found in the breasts, salivary lacrimal glands, gastric mucosa, and ovaries (14,15). However, concerns have been raised regarding radioactive iodine therapy, because of the potential for the development of second primary malignancy, including breast cancer (16).…”