**2. Iodide metabolism in the thyroid follicular cell**

Iodine is an essential constituent of thyroid hormones. Therefore, a fundamental condition for normal thyroid hormonogenesis is that iodide—an extremely scarce environmental micronutrient—should be made available in sufficient amounts to the thyroid follicular cells (also known as thyrocytes), which have developed a remarkably efficient and specialized iodide-handling system. Under physiological conditions, the thyroid gland accumulates iodide al concentrations up to 40 times those in the plasma. The sodium/iodide symporter (NIS) is the key plasma membrane glycoprotein, which is located at the basolateral surface of the thyroid follicular cell that mediates active iodide transport from the bloodstream to the thyroid follicular cells in the first step and the rate-limiting step of thyroid hormonogenesis [11]. The carboxy-terminus of the protein, which is oriented toward the cytoplasm, contains specific sorting and retention signals required for NIS expression at the basolateral plasma membrane [12–15]. NIS-mediated active iodide transport is electrogenic and couples the inward translocation of one iodide ion against its electrochemical gradient to the inward transport of two sodium ions down its electrochemical gradient, generated by the sodium/potassium ATPase [16]. Remarkably, NIS transports iodide efficiently at the submicromolar concentrations found in the bloodstream, by taking advantage of the physiological sodium concentration [17]. Therefore, the mechanism of NIS-mediated iodide transport seems to be an evolutionary adaptation to the scant amount of iodide in the environment.

#### *The Molecular Basis for Radioiodine Therapy DOI: http://dx.doi.org/10.5772/intechopen.108073*

In addition to the different radioiodide isotopes, NIS can translocate a variety of clinically relevant radionuclide substrates. These include 99mTc-pertechnectate or 18F-tetrafluoroborate, which facilitates noninvasive diagnostic imaging, and also 188Re-perrhenate, which allows therapeutic destruction of tumor tissue through the radionuclide accumulation of NIS-expressing cells and the bystander effect induced by the crossfire effect of beta emission [10].

Underscoring the significance of NIS for thyroid physiology, several naturally occurring loss-of-function NIS variants have been identified as causes of the uncommon autosomal recessive disorder iodide transport defect, which results in dyshormonogenic congenital hypothyroidism due to insufficient iodide availability for thyroid hormonogenesis [9]. Moreover, a recent study speculated that pathogenic variants may exist in yet to be discovered thyroid-specific genes and are likely to be required for NIS-mediated iodide transport in the thyroid follicular cell [18]. In line with this hypothesis, the KCNQ1/KCNE2 potassium channel has been shown to be required for adequate NIS-mediated iodide accumulation in the thyroid tissue [19, 20]. The detailed functional characterization of loss-of-function NIS variants identified in patients has provided mechanistic information about the transporter. Remarkably, several amino acid residues have been identified as being critical for substrate binding, specificity, and stoichiometry, as well as for folding and plasma membrane targeting [21–28].

Once iodide has reached the cytosol of the thyroid follicular cells, the iodide is then handled by a sophisticated thyroid-specific iodine-metabolizing machinery that covalently incorporates (also named organification) iodine into tyrosine residues of thyroglobulin, which permits further thyroid hormone synthesis [29]. Significantly, the normal function of this iodide-metabolizing machinery is not only critical for thyroid hormonogenesis, but also for successful radioiodine ablation of cancer cells, as the covalent incorporation of radioiodine into thyroglobulin increases the residence time of the radioisotope.
