T3 hormone

Thyroid hormone receptor, T3R 3,5,3 -L- triiodothyronine, T3 hormone RGGTCA IR-0, DR-4, ER-6,8... 

Fig. 4.6. HRE structure of the RXR heterodimer. Shown is the consensus sequence of the HREs of the RXR heterodimers (see Fig. 4.7) and the different possible arrangements of the hexameric half-site sequences. The hexamers can be arranged palindromically as inverted repeats (a), as everted repeats (b), or as direct repeats (c). n indicates the number of base pairs that lie between the two hexamers. RXR receptor for 9-ds retinoic acid RAR receptor for all-trans retinoic acid T3R receptor for the T3 hormon PPAR peroxisome prohferator-activated receptor VDR receptor for vitamin D3.

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. 

Ligands of the RXR-heterodimer group and the orphan receptors are chemically more diverse than the ligands of the steroid family. Representative hgands of this group are the retinoids all-trans retinoic acid, 9-cis retinoic acid, the T3 hormone and vitamin D3 (fig. 4.1). 

A further, more dramatic difference to the steroid hormone receptors is the localization of the receptors. The receptors for the retinoids (RAR and RXR, see table 4.1), the T3 hormone (T3R) and vitamin D3 (VDR) are mainly localized in the nucleus and their activity is not controlled by the heat shock proteins. The receptors also bind the corresponding HRE in the absence of hormone, in which case they can then act as repressors of gene activity. In the presence of the hormone an activation of gene expression is usually observed. 

Fig. 4.11. Principle of signal transduction by RXR heterodimers. The activated hormone can be made available to the RXR heterodimer in three different ways, a) The hormone (e.g. T3 hormone) is synthesized in endocrinal tissue and reaches the DNA-bound RXR-T3R heterodimer in the nucleus via passive transport, b) The active hormone is formed in the cytosol from an inactive apo-hormone (as for, e.g. 9-ds-retinoic add), c) The hormone is synthesized intracellularly. In aU three cases, the binding of the hormone-RXR-heterodimeric complex is the signal that induces transcription activation of the downstream genes. After Mangelsdorf and Evans, 1995.

There is an altogether complex interaction between HRE, receptor and hormone in the group of receptors for retinoids, vitamin D3 and the T3-hormone. The complexity is determined by the following factors ... 

Target organ T4/T3 hormone Cortisol Oestradiol Testosterone IGF-1... 

Studies that examined relationships between PCB exposure and thyroid hormone status in children or adults reported a variety of different results, with findings of both positive and negative correlations between PCB exposure and circulating levels of thyroid stimulating hormone (TSH) or thyroxine (T4) or triiodothyronine (T3) hormones. 

M (altered thyroid follicular ultrastructure, increased serum T3 hormone)... 

Triiodothyronine, T3-Hormon Increased oxygen consumption and increased heat formation,... 

Fig. 4.11 Model of repression and activation of T3R. In the absence of the T3 hormone, a hetero-dimeric RXR-T3R receptor is bound at the T3-re-sponsive element,TRE, establishing a basal repressed state. The repressed state is maintained by recruitment of corepressor complexes containing histone deacetylase activity. X refers to potential unidentified cofactors (possibly chromatin remodeling complexes or SRBs) which help to keep the promotor-bound basal transcription apparatus in...

The latter point is of importance in the hypothalamus-pituitary system of the brain, where feedback inhibition at various levels is used to prevent overproduction of, e.g., steroid hormones or the T3 hormone. 

Based on the receptor activation mechanism, the nuclear receptors may be divided into two basic groups. In the first group (those including most of the steroid hormone receptors), the receptors can be localized in the nucleus or in the cytoplasm. The receptors of the other group (discussed in Section 4.7) are always localized in the nucleus. Representative ligands of these receptors are the derivatives of retinoic acid, the T3 hormone and VitD3. 

As already illustrated in Fig. 4.5, the receptors of all-trans retinoic acid, 9-cis retinoic acid, vitamin D3 and the T3-hormone usually bind their HREs preferentially in the form heterodimers. 

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