Thyroid hormones cell specificity

Bassett JH, Harvey CB, Williams GR. Mechanisms of thyroid hormone receptor-specific nuclear and extra nuclear actions. Mol Cell Endocrinol. 2003 213 1-11. 

A recently identified thyroid hormone cell surface receptor on the extracellular domain of integrin alphaVbeta (3) leads to the activation of the mitogen-activated protein kinase (MAPK) signal transduction cascade in human cell lines, Examples of MAPK-dependent thyroid hormone actions are plasma membrane ion pump stimulation and specific nuclear events, These events include serine phosphorylation of the nuclear thyroid hormone receptor, leading to co-activator protein recruitment and complex tissue responses, such as thyroid hormone-induced angiogenesis, The existence of this cell surface receptor means that the activity of the administered hormone could be limited through structural modification of the molecule to reproduce only those hormone actions initiated at the cell surface (8,9). 

Only small amounts of free T are present in plasma. Most T is bound to the specific carrier, ie, thyroxine-binding protein. T, which is very loosely bound to protein, passes rapidly from blood to cells, and accounts for 30—40% of total thyroid hormone activity (121). Most of the T may be produced by conversion of T at the site of action of the hormone by the selenoenzyme deiodinase (114). That is, T may be a prehormone requiring conversion to T to exert its metaboHc effect (123). 

A model of thyroid hormone action is depicted in Figure 38-4, which shows the free forms of thyroid hormones, T4 and T3, dissociated from thyroid-binding proteins, entering the cell by active transport. Within the cell, T4 is converted to T3 by 5 -deiodinase, and the T3 enters the nucleus, where T3 binds to a specific T3 receptor protein, a member of the c-erb oncogene family. (This family also includes the steroid hormone receptors and receptors for vitamins A and D.) The T3 receptor exists in two forms, a and B. Differing concentrations of receptor forms in different tissues may account for variations in T3 effect on different tissues. 

Water-insoluble hormones (steroid, retinoid, and thyroid hormones) readily pass through the plasma membrane of their target cells to reach their receptor proteins in the nucleus (Fig. 23-4). With this class of hormones, the hormone-receptor complex itself carries the message it interacts with DNA to alter the expression of specific genes, changing the enzyme complement of the cell and thereby changing cellular metabolism (see Fig. 12 10). 

Steroid, vitamin D, retinoid, and thyroid hormones enter target cells and alter gene expression by interacting with specific nuclear receptors. 

Steroid hormones penetrate the cell and bind to receptors in the nucleus, and activate (or sometimes repress) transcription of specific genes. Thyroid hormones act similarly. 

Nuclear Hormone Receptors. Certain hormones interact directly with hormonal receptors that are located on the chromatin within the cell nucleus (see Fig. 28-2).3 Thyroid hormones (T3 and T4) are a primary example of hormones that bind directly to nuclear receptors.29 After binding, thyroid hormones invoke a series of changes similar to those caused by the steroid-cytosolic receptor complex that is, the nucleus begins to transcribe messenger RNA, which is ultimately translated into specific proteins. In the case of the thyroid hormones, these new proteins usually alter the cell s metabolism. Thyroid hormones are discussed in more detail in Chapter 31. 

Little is known about the mechanism of action of thyroid hormones on microtubule assembly. It might be that, as in other cell types, thyroid hormones regulate the expression of the specific TAU mRNAs and/or their accumulation. One has also to take into account that a large number of other molecules are required to build up neurites during neuronal differentiation (membranes, components of the growth cone, etc.). 

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