Content Reviewers:Rishi Desai, MD, MPH
They’re two tyrosine-based iodine-containing hormones that help regulate our body’s metabolism.
T3 and T4 are produced by the thyroid gland, which is located in the neck and consists of two lobes that look like two thumbs hooked together in the shape of a “V”.
If we zoom into the thyroid gland, we’ll find thousands of follicles, which are small hollow spheres whose walls are lined with follicular cells or thyrocytes, and are separated by a small amount of connective tissue.
Follicular cells are bipolar cells - with an apical side that surrounds a central cavity or lumen filled with the colloid, which is a fluid that contains the precursor hormone thyroglobulin.
Thyroglobulin is a large glycoprotein that is synthesized by the follicular cells and then it is secreted into the lumen of the follicle to be stored in the colloid.
The basolateral side of follicular cells is in contact with blood vessels.
The basolateral membrane contains a sodium-iodide symporter, which pumps two sodium ions into the cell down their electrochemical gradient, in order to bring one iodide ion into the cell from blood.
Iodide is then pumped into the colloid through an ion transporter called pendrin, which exchanges iodide for chloride, since they’re both negatively charged.
Once iodide is in the colloid, it undergoes oxidation with the enzyme thyroperoxidase, which changes it into an iodine atom.
It’s then attached to tyrosine amino acid residues which are found throughout thyroglobulin.
This process is called iodination.
Some tyrosine residues are bound by only one iodine, whereas others are bound by two iodine atoms, yielding monoiodotyrosine or MIT, and diiodotyrosine or DIT, respectively.
These molecules are then linked together by thyroperoxidase.
Linking one MIT with one DIT creates T3, while linking two DIT molecules creates T4 - and both T3 and T4 remain bound to thyroglobulin.
You see - thyroglobulin basically serves as a peptide that stores these hormones on it in the colloid, until it’s ready to be used. T4 is created in greater amounts than T3.
When the follicular cells are ready to secrete T3 and T4, they endocytose the thyroglobulin into a vesicle which then fuses with the lysosome.
Here, thyroglobulin is cleaved by proteases, and T3 and T4 are released right into the bloodstream through the monocarboxylate or MCT transporter.
T3 is the highly active form with a half life of one to two days, while T4 is the less active form with a longer half life of six to eight days.
Production and secretion of thyroid hormones is under control of the hypothalamus-pituitary axis.
The hypothalamus, which is located at the base of the brain, secretes thyrotropin releasing hormone, or ΤRH, into the hypothalamo- hypophyseal portal system - which is a network of capillaries linking the hypothalamus to the anterior pituitary.
In the anterior pituitary, TRH binds to a surface protein on a group of pituitary cells, called thyrotroph cells, and stimulates them to release the hormone thyrotropin, also called thyroid stimulating hormone or simply TSH, into the bloodstream.
TSH then travels to the thyroid gland, and binds to the TSH receptors located in the membrane of the follicular cells of the thyroid gland.
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