Minireview: The sodium-iodide symporter NIS and pendrin in iodide homeostasis of the thyroid

Abstract

Thyroid hormones are essential for normal development and metabolism. Thyroid hormone biosynthesis requires iodide uptake into the thyrocytes and efflux into the follicular lumen, where it is organified on selected tyrosyls of thyroglobulin. Uptake of iodide into the thyrocytes is mediated by an intrinsic membrane glycoprotein, the sodium-iodide symporter (NIS), which actively cotransports two sodium cations per each iodide anion. NIS-mediated transport of iodide is driven by the electrochemical sodium gradient generated by the Na(+)/K(+)-ATPase. NIS is expressed in the thyroid, the salivary glands, gastric mucosa, and the lactating mammary gland. TSH and iodide regulate iodide accumulation by modulating NIS activity via transcriptional and posttranscriptional mechanisms. Biallelic mutations in the NIS gene lead to a congenital iodide transport defect, an autosomal recessive condition characterized by hypothyroidism, goiter, low thyroid iodide uptake, and a low saliva/plasma iodide ratio. Pendrin is an anion transporter that is predominantly expressed in the inner ear, the thyroid, and the kidney. Biallelic mutations in the SLC26A4 gene lead to Pendred syndrome, an autosomal recessive disorder characterized by sensorineural deafness, goiter, and impaired iodide organification. In thyroid follicular cells, pendrin is expressed at the apical membrane. Functional in vitro data and the impaired iodide organification observed in patients with Pendred syndrome support a role of pendrin as an apical iodide transporter.

Figure 1

Main steps in thyroid hormone synthesis. At the basolateral membrane of thyroid follicular cells, which form the follicles, iodide is transported into thyrocytes by the NIS. NIS is dependent on the sodium gradient created by the Na/K-ATPase. At the apical membrane, iodide efflux is, in part, mediated by pendrin (PDS/SLC26A4). At the cell-colloid interface, iodide is oxidized by TPO in the presence of H₂O₂. H₂O₂ is produced by the calcium- and reduced nicotinamide adenine dinucleotide phosphate-dependent (NADPH) enzyme DUOX2. DUOX2 requires a specific maturation factor, DUOXA2. Thyroglobulin (TG), which is secreted into the follicular lumen, serves as matrix for synthesis of T₄ and T₃. First, TPO catalyzes iodination of selected tyrosyl residues (organification), which results in the formation of MIT and DIT. Subsequently, two iodotyrosines are coupled to form either T₄ or T₃ in a reaction that is also catalyzed by TPO. Iodinated thyroglobulin is stored as colloid in the follicular lumen. Upon a demand for thyroid hormone secretion, thyroglobulin is internalized into the follicular cell by pinocytosis and digested in lysosomes, which generates T₄ and T₃ that are released into the bloodstream through unknown mechanisms. The unused MIT and DIT are retained in the cell and deiodinated by the iodotyrosine dehalogenase 1 (DEHAL1). The released iodide is recycled for thyroid hormone synthesis.