Thyroid hormone secretion involves the internalization of iodinated thyroglobulin and the movement of endocytotic vesicles from the apical to basal surface. These vesicles then fuse with lysosomes, where thyroglobulin undergoes enzymatic degradation by lysosomal enzymes. This degradation releases thyroid hormones from the thyroglobulin backbone. The thyroid hormones are then transported across the basolateral membrane, potentially through a specific transporter, and eventually enter the bloodstream. Thus, the secretion process entails apical-to-basal movement.

The synthesis of iodothyronines on a thyroglobulin backbone begins with the active transport of iodide into the thyroid gland against chemical and electrical gradients. This transport is facilitated by a sodium-iodide symporter (NIS) located on the basolateral membrane of thyroid epithelial cells. NIS is predominantly expressed in the thyroid gland but is also found at lower levels in the placenta, salivary glands, and lactating breast. The NIS transporter uses the energy provided by the plasma membrane Na+,K+-ATPase to move one iodide ion uphill against an iodide gradient, while two sodium ions move down their electrochemical gradient from the extracellular fluid into the thyroid cell. The expression of the NIS gene is inhibited by iodide and stimulated by thyroid-stimulating hormone (TSH). When dietary iodide intake is reduced, the circulating iodide pool becomes depleted, significantly enhancing the activity of the iodide trap. In such cases, the percentage of thyroid uptake of iodide can reach 80% to 90%.

The steps involved in thyroid hormone synthesis are depicted in Figure 42.6. Once iodide enters the gland, it quickly moves to the apical plasma membrane of epithelial cells. From there, a sodium-independent iodide/chloride transporter called pendrin facilitates the transport of iodide into the lumen of the follicles. In the follicular lumen, iodide is rapidly oxidized and incorporated into tyrosine residues within thyroglobulin. A single iodination leads to the formation of monoiodotyrosine (MIT), while a second iodination of the same residue results in diiodotyrosine (DIT). After iodination, two DIT molecules combine to form thyroxine (T4), whereas one MIT and one DIT combine to produce triiodothyronine (T3). The coupling occurs between iodinated tyrosines that remain part of the primary structure of thyroglobulin.

The iodothyronines T4 (3,5,3',5'-tetraiodothyronine or thyroxine), T3 (3,5,3'-triiodothyronine), and reverse T3 (3,3',5'-triiodothyronine) possess the structures shown in Figure 42.3. Outer ring deiodination activates the hormone, while inner ring deiodination inactivates it. Deiodinases type 1 and 2 are involved in the former process, while deiodinase type 3 mediates the latter.
Synthesis of Iodothyronines on ). Secretion of thyroid hormone involves endocytosis of iodinated thyroglobulin and apicalto-basal movement of the endocytotic vesicles, which fuse with lysosomes. Thyroglobulin is enzymatically degraded by lysosomal enzymes, resulting in release of thyroid hormones from the thyroglobulin backbone. Finally, thyroid hormones move across the basolateral membrane, probably through a specific transporter, and ultimately into the blood. Thus secretion involves apical-to-basal movement (see
Fig. 42.5
Synthesis of Iodothyronines on a Thyroglobulin Backbone
Iodide is actively transported into the gland against chemical and electrical gradients by a sodium-iodide symporter (NIS) located in the basolateral membrane of thyroid epithelial cells (see
Fig. 42.5 ). NIS is highly expressed in the thyroid gland, but it is also expressed at lower levels in the placenta, salivary glands, and actively lactating breast. One iodide ion is transported uphill against an iodide gradient while two sodium ions move down their electrochemical gradient from extracellular fluid into the thyroid cell. The driving force for this secondary active transporter is provided by plasma membrane Na+,K+-ATPase. Expression of the NIS gene is inhibited by iodide and stimulated by TSH. A reduction in dietary iodide intake depletes the circulating iodide pool and greatly enhances the activity of the iodide trap. When dietary iodide intake is low, the percentage of thyroid uptake of iodide can reach 80% to 90%.
The steps in thyroid hormone synthesis are shown in
Fig. 42.6 . After entering the gland, iodide rapidly moves to the apical plasma membrane of epithelial cells. From there, iodide is transported into the lumen of the follicles by a sodium-independent iodide/chloride transporter called pendrin. Iodide is immediately oxidized and incorporated into tyrosine residues within thyroglobulin (see
Fig. 42.5 ). A single iodination forms a monoiodotyrosine (MIT); a second iodination of the same residue produces diiodotyrosine (DIT) (see
Fig. 42.6 ). After iodination, two DIT molecules are coupled to form T4; one MIT and one DIT are coupled to form T3. Coupling occurs between iodinated tyrosines that remain part of the primary structure of
I I 3,5,3¢ 5¢ -Tetraiodothyronine (thyroxine, or T4) NH2 HO O CH2CHCOOH Outer ring deiodination (activation) Inner ring deiodination Deiodinases type 1 and 2 I I Deiodinases type 3 I 3,5,3¢ -Triiodothyronine (T3) I NH2 CH2CHCOOHO (inactivation) I I 3,3¢ 5¢ -Triiodothyronine (reverse T3) NH2 CH2CHCOOHHO O •Fig. 42.3 StructureoftheiodothyroninesT4,T3,andreverseT3.