The thyroid gland is located in the throat, directly inferior and anterior to the larynx. It sits like a bow tie across the larynx and is composed of two lobes connected by an isthmus. If we examined a magnified version of the thyroid gland, we would see that it is divided into segments called follicles in which the thyroid hormones are produced. The thyroid gland produces two hormones, triiodothyronine, referred to as T3, and tetraiodothyronine, also called T4 or thyroxine. The thyroid gland produces mostly T4, around 90%, but T3 is about 4 times more potent than T4. Thyroid hormone production has both intracellular and extracellular components. If we examined a thyroid follicle, we would see that it is filled with a protein-rich material called colloid. Follicular cells surround the centralized colloid and secrete proteins into it. The follicular cells are closely associated with capillaries, which are used to deliver iodide molecules to the cells. Iodide molecules are obtained from the diet and are essential to the production of thyroid hormones. The capillaries are also an important release site for the thyroid hormones once they are produced. The follicular cells have polarized membranes, meaning that there are different transport proteins available on the apical and basolateral membranes. The apical membrane faces the lumen of the follicle where the colloid is stored. The basolateral membrane of the follicular cell faces the surrounding capillaries. In order to thoroughly discuss the production of thyroid hormones, we will need to zoom in on a magnified version of the follicular cells. The follicular cells are represented by yellow rectangles in the center of the screen with the basolateral membrane facing down towards the capillary. The apical membrane of the follicular cells is located at the top, facing the colloid. The two thyroid hormones, T3 and T4, are produced by the thyroid follicles using a protein called thyroglobulin and iodide molecules from the diet. The first step in thyroid hormone synthesis is the trapping of iodide molecules from the diet. Iodide is absorbed from the GI tract and travels through the bloodstream to thyroid follicular cells. The follicular cells take up the iodide through their basolateral membrane using a sodium iodide symporter. This is an example of secondary active transport, as the symporter uses the sodium gradient to pump iodide ions against their concentration gradient into the cell. Follicular cell vesicles contain the enzyme thyroid peroxidase. This enzyme oxidizes the iodide anion into iodine. While the follicular cells are trapping the iodide, the glycoprotein thyroglobulin is being synthesized by follicular cells. The thyroglobulin travels through the secretory pathway from the ER into the Golgi body and is packaged into secretory vesicles. These secretory vesicles then fuse with the apical membrane of the follicular cell, releasing thyroglobulin into the colloid. The thyroglobulin protein, which is now inside the colloid, can become iodinated at tyrosine residues at this time. Each tyrosine can have one iodine added to form T1 or two iodines added to it to form T2. During the last step of synthesis, a T1 and T2 molecule join to form T3 or two T2 molecules join to form T4. The joining of two T2 molecules forms the thyroid hormone T4, also called thyroxine. The joining of a T1 and T2 molecule forms triiodothyronine or T3. Remember that at this time the thyroid molecules are still attached to the thyroglobulin backbone. These mature thyroid hormones can be stored in the colloid until needed by the body. In order to release the thyroid hormones into the bloodstream during times of need, thyroglobulin and its iodinated tyrosines undergo endocytosis and enter the follicular cell. This vesicle then fuses with a lysosome, forming an endolysosome. Digestive enzymes inside the lysosome break down the thyroglobulin backbone, releasing the T3 and T4. T3 and T4 then diffuse across the basolateral membrane into the bloodstream. Once in the bloodstream, the thyroid hormones require transporter proteins such as thyroxine-binding globulins. Over 99% of the thyroid hormones within the bloodstream are bound to transporter proteins. As mentioned previously, approximately 90% of the secretory product is T4. However, T4 is converted at peripheral tissues into the more active T3 hormone. When T4 arrives at a target cell, it diffuses out of the blood vessel and into the interstitial fluid, leaving the transport protein thyroxine binding globulin behind. The T4 then diffuses across the plasma membrane. Once in the cytosol, T4 is converted into the more active T3 form by the enzyme monodeiodinase. T3 then diffuses into the nucleus. and binds to a thyroid hormone receptor. This complex binds to the thyroid hormone response element and initiates nuclear transcription and cytosolic translation. The protein product shown here as a sodium-potassium pump would then be able to initiate the effects of the hormone.