The Na+/I- symporter (NIS) is an integral plasma membrane glycoprotein commonly discussed in connection with the thyroid gland, where NIS mediates the active transport of iodide into the thyroid follicular cells, the crucial first step in the biosynthesis of the only iodine-containing hormones in vertebrates, the thyroid hormones. NIS is basolaterally expressed in the thyroid and in many other tissues, including lactating breast, salivary glands, and gastric mucosa.
Iodine is extremely scarce in the environment and can only be obtained through the diet. Therefore, dietary iodide absorption in the gastrointestinal tract constitutes the first step in iodide metabolism. The question of where and how dietary iodide is absorbed has long been of major interest. We have identified functional NIS expression along the entire length of the small intestinal epithelium, and postulated it as the central component of the iodide absorption system. Interestingly, NIS expression was clearly apparent exclusively on the apical surface of the enterocytes (in contrast to the basolateral expression in the aforementioned tissues), consistent with the notion that NIS may transport iodide from the intestinal lumen towards the bloodstream.
Under physiological conditions, NIS concentrates iodide by coupling the inward transport of Na+ down its electrochemical gradient to the translocation of I- against its electrochemical gradient. NIS-mediated transport of iodide is electrogenic, coupling the transport of 2 Na+ cations and 1 I- anion. We have recently shown that NIS translocates different substrates with different stoichiometries, as NIS-mediated transport of perrhenate (ReO4-) or the environmental pollutant perchlorate (ClO4-) is electroneutral. Mechanistic information has been obtained by characterizing congenital I- transport defect–causing NIS mutants. One of these, G93R NIS, is targeted to the plasma membrane but is inactive, and led us to conduct a detailed study of position 93. We observed that the longer the side chain of the neutral residue substituted at this position, the lower the activity of the protein, and the higher the Km for the anion substrates. Strikingly, unlike NIS, which mediates electroneutral Na+/ReO4- or ClO4- symport, G93T NIS transports these anions electrogenically with a 2:1 stoichiometry. Surprisingly, although G93E NIS exhibited no apparent I- transport activity, it clearly exhibited ReO4- transport, suggesting that this position can discriminate substrates. Based on the 3-D structure of the bacterial Na+/galactose transporter, we built a 3-D homology model of NIS and propose a mechanism in which changes from an outwardly to an inwardly open conformation during the transport cycle use G93 as a pivot.
