T3, nuclear receptors

A second type of mechanism is illustrated by the malic enzyme and fatty synthetase systems. In such systems the effect of T3 on the accumulation of the specific mRNAs does not seem to depend only on direct gene activation by the T3-nuclear receptor. An amplification post-transcriptional mechanism seems to contribute to the accumulation of the specific mRNAs. Stabilization of the mRNA level is also differently modulated by other hormones and by the diet. 

Among the essential trace elements, Zn has the greatest number and variety of functions in hundreds of enzymes. In spite of the fact that Zn ions are redox inert in biology, they have profound effects on redox metabolism. Thus, both Zn deficiency and Zn overload elicit oxidative stress that can lead to the death of nerve cells (Hao and Maret, 2006). The thyroid requires the presence of some essential elements other than 1 for the synthesis of thyroid hormones, for example Fe, Zn and Se (Zimmermann and Kohrle, 2002). Thyroid hormones exert their effects through nuclear receptors, and the T3 nuclear receptor is a Zn-containing protein (Miyamoto, 1991). 

The analysis of the properties of the T3 nuclear receptors during development reveals several interesting features ... 

Ph. De Nayer and B. Dozin. Thyroid hormones and brain development modulation of the binding activity of the T3 nuclear receptor by chromatin-associated factors. Molec. Physiol. 7 303-310 (1985). 

Triiodothyronine (3, 5,3-L-triiodothyronine, T3) is a thyroid hormone. It is producedby outer ring deiodination of thyroxine (T4) in peripheral tissues. The biologic activity of T3 is 3-8 times higher than that of T4. T3 is 99.7% protein-bound and is effective in its free non-protein-bound form. The half-life of triiodothyronine is about 19 h. The daily tur nover of T3 is 75%. Triiodothyronine acts via nuclear receptor binding with subsequent induction of protein synthesis. Effects of thyroid hormones are apparent in almost all organ systems. They include effects on the basal metabolic rate and the metabolisms of proteins, lipids and carbohydrates. 

The initial step after cellular uptake of T4 is metabolic transformation to 3,5,3, -tri-iodothyronine (T3) (Fig. 52-8), which interacts with cytosolic and nuclear receptors, as well as with synaptosomal membrane binding sites of unknown function [25], Cytosolic receptors are proteins of 70 kDa that do not appear to undergo translocation to cell nuclei, nor do they appear to be nuclear proteins that have leaked out of cell nuclei during cell rupture nuclear receptors are proteins of 50 70 kDa that have both DNA-and hormone-binding domains [25,26,28],... 

The DNA binding element of the nuclear receptors for all-trans retinoic acid, for 9-cis retinoic acid, for the T3 hormone and for the vitamin D3 hormone usually exhibit a direct repeat of the recognition sequence, resulting in formation of heterodimers on the DNA (fig. 4.7b). One of the partners in the heterodimer is always the receptor for 9-cis retinoic acid, RXR, and which usually occupies the 5 side of the HRE. 

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. 

Fig. 2. Early events in thyroid-hormone action. Interaction of T3 with cell nuclear receptors (6).

Most of the hormonal activities of thyroid hormones result from the binding of T3 to chromatin-associated nuclear receptors. Recent evidence suggests that, in several cells, translocation of T3 and T4 from plasma to the intracellular compartment is accomplished by a receptor-mediated, limited capacity, active transport system37. In hepatocytes, it has also been shown that an energy-dependent stereospecific active transport system is involved in the translocation of T3 from the cytosol into the nucleus38,39. 

Representatives of non-steroidal ligands, binding to nuclear receptors are T4 (tetra-iodothyronine thyroxine) and T3 (tri-iodothyronine) (Fig. 11.9). 

The observation that in the 3 -substituted structures the hydrogen bonding atom approaches the 4 -0H trans to the 3 -substituent is verification of quantitative structure activity relationship (QSAR) data which also suggest that in vitro binding of T3 probably involves hydrogen bond donation of the 4 -OH to the 5 -side of the nuclear receptor (28). 

Nuclear receptors, which bind triiodothyronine (T3) after it enters the cell ... 

The nuclear receptor for T3 belongs to the same superfamily as steroid hormone receptors, especially in their DNA-binding domains and in the organization of their functional domains, which appear to correlate with similarities in their mechanism of action.139-141... 

Since L-tryptophan has been demonstrated to have a specific nuclear receptor in liver,78-80 it was important to consider whether its receptor may be similar or related to other hormone-related hepatic nuclear receptors. Triiodothyronine (T3) receptors and glucocorticoid receptors are part of a group... 

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