Mechanism of Thyroid Hormone Action

Thyroid Factor

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As previously discussed, the major hormone secreted by the thyroid gland is thyroxine, or tetraiodothyronine (T4). Like steroid hormones, thyroxine travels in the blood attached to carrier proteins (primarily to thyroxine-binding globulin, or TBG). The thyroid also secretes a small amount of triiodothyronine, or T3. The carrier proteins have a higher affinity for T4 than for T3, however, and, as a result, the amount of unbound (or "free") T3 in the plasma is about ten times greater than the amount of free T4.

Approximately 99.96% of the thyroxine in the blood is attached to carrier proteins in the plasma; the rest is free. Only the free thyroxine and T3 can enter target cells; the protein-bound thyroxine serves as a reservoir of this hormone in the blood (this is why it takes a couple of weeks after surgical removal of the thyroid for the symptoms of hypothyroidism to develop). Once the free thyroxine passes into the target cell cytoplasm, it is en-zymatically converted into T3. As previously discussed, it is the T3 rather than T4 that is active within the target cells.

Unlike many of the steroid receptors, the inactive receptor proteins for T3 are located in the nucleus. Until they bind to T3, however, the receptors are incapable of binding to DNA and stimulating transcription. The T3 may enter the cell from the plasma, or it may be produced in the cell by conversion from T4. In either case, it uses some nonspecific binding proteins as "stepping stones" to enter the nucleus, where it binds to the ligand-binding domain of the receptor (fig. 11.6). Once the receptor binds to T3, its DNA-binding domain can attach to the half-site of the DNA hormone-response element.

The other half-site, however, does not bind to another T3 receptor protein. Unlike the steroid hormone receptors, the nuclear receptors in the nonsteroid family bind to DNA as heterodimers. The thyroid hormone receptor (abbreviated TR) is one partner in the heterodimer; the other partner is a receptor (abbreviated RXR) for the vitamin A derivative 9-cis-retinoic acid. Once bound to their different ligands, the two partners in the heterodimer can bind to the DNA to activate the hormone-response element for thyroid hormone (fig. 11.7). In this way, thyroid hormones stimulate transcription of genes, production of specific mRNA, and therefore the production of specific enzymes (see fig. 11.6).

Interestingly, the receptor for 1,25-dihydroxyvitamin D3, the active form of vitamin D, also forms heterodimers with the receptor for 9-cis-retinoic acid (the RXR receptor) when it binds

Mechanisms Hormones Action

RXR receptor

(for 9-cis retinoic acid) -

Blood Target cell

RXR receptor

(for 9-cis retinoic acid) -

Blood Target cell

■ Figure 11.6 The mechanism of action of thyroid hormones on the target cells. T4 is first converted into T3 within the cytoplasm of the target cell. T3 then enters the nucleus and binds to its nuclear receptor. The hormone-receptor complex can then bind to a specific area of DNA and activate specific genes.

to DNA and activates genes. The RXR receptor and its vitamin A derivative ligand thus form a link between the mechanisms of action of thyroid hormone, vitamin A, and vitamin D, along with those of some other molecules that are important regulators of genetic expression.

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Essentials of Human Physiology

Essentials of Human Physiology

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