Most biological actions of T3 are initiated by its binding to nuclear T3 receptors. These proteins are members of the superfamily of ligand- dependent transcription factors, which also includes the receptors for steroids (e.g. cortisol, oestradiol, and testosterone), 1,25- dihydroxyvitamin D3, retinoic acid, and 9- cis- retinoic acid. The last, so- called retinoid X receptor (RXR) is an important member of this gene family, because it forms functional heterodimers with a number of other nuclear receptors, including T3 receptors. Two T3 receptor genes have been identified; the THRA gene encoding TRα is located on human chromosome 17 and the THRB gene encoding TRβ on human chromosome 3. By alternative exon utilization of both genes, four major receptor isoforms, TRα1, TRα2, TRβ1, and TRβ2, are generated, which consist of 410– 514 amino acids (Figure 1). Although the THRB gene (150 kb) is much larger than the THRA gene (c.30 kb), they have similar genomic structures, comprising 10 (THRB) or 11 (THRA) exons, and their coding sequences show a high degree of homology.

Fig1. Domain structures of the different T3 receptor (TR) isoforms. The TRα2 variant is incapable of binding T3 . DBD, DNA- binding domain; LBD ligand- binding domain.

As in the other members of the nuclear receptor family, functional key domains have been recognized in the T3 receptors, in particular the DNA- binding domain (DBD), which is approximately 100 amino acids long, and the ligand- binding domain (LBD), which is approximately 250 amino acids in length. The amino acid sequences of the TRα and TRβ subtypes are most homologous in their DBD and LBD and least homologous at their N- terminus. The latter contains the ligand- independent AF1 transactivation domain, while an AF2 domain necessary for homo- and heterodimerization and ligand- dependent activation is located at the C- terminus. The short sequence between the DBD and the LBD is usually referred to as the hinge region.

T he structural difference between TRα1 and TRα2 is located at the C- terminus of the proteins, where the sequences of the last 40 amino acids in TRα1 and 122 amino acids in TRα2 differ completely due to alternative splicing. The alteration in the LBD of TRα2 is associated with a complete loss of T3 binding. Therefore, this splice variant is not a bona fide T3 receptor, but for convenience it will still be referred to here as TRα2. TRα2 has a weak negative effect on the action of T3 through the other T3 receptors. The N- terminal domains of TRβ1 (106 amino acids) and TRβ2 (159 amino acids) differ almost completely due to utilization of alternative transcription start sites. Apparently, this domain provides TRβ2 with specific properties required for T3- induced downregulation of TRH and TSH genes.

The high homology between the LBDs of TRα1 and TRβ explains their very similar ligand specificity, with affinities much higher for T3 than for T4. However, the metabolite Triac also binds to the T3 receptors with an affinity equal to (TRα1) or even greater than (TRβ1) that of T3. Nevertheless, T3 is the major endogenous iodothyronine occupying the nuclear thyroid hormone receptors, which are thus true T3 receptors. Several TRβ- specific agonists have been developed with pharmacologically interesting and selective effects on the liver, resulting in lowering of body weight, lipid, and cholesterol without detrimental effects on the heart. Most likely, the tissue- specific effects of these compounds are not only determined by their affinity for the T3 receptor isoforms but also by the diverse ligand- preference of thyroid hormone transporters in different tissues. Interestingly, non- selective T3 receptor antagonists have been developed as well.

The different T3 receptor isoforms show distinct tissue distributions. The TRα1 is the predominant T3 receptor expressed in brain, heart, and bone, whereas TRβ1 is the major receptor in other tissues, including liver, skeletal muscle, kidney, and fat. TRβ2 is preferentially expressed in the anterior pituitary and the hypothalamic area of the brain. These locations suggest the particular involvement of TRβ2 in the feedback inhibition of TSH and TRH secretion by thyroid hormone. Exon utilization specifying TRβ2 expression in the anterior pituitary is under the control of pituitary- specific transcription factor 1, response elements for which are located in the TRβ gene promoter. Regulation of the expression of T3- responsive genes involves the binding of the T3 receptors to so- called T3 response elements (TREs) in the promoter region of these genes. TREs usually consist of two half- sites arranged as repeats or palindromes. The most prevalent TRE half- site sequence is AGGTCA, and the direct repeat of this half- site spaced by four nucleotides (DR4) is a particularly powerful TRE. However, some TREs show marked deviation from this ‘consensus’ half- site sequence, which, moreover, is also recognized by other receptors such as RXR and the retinoic acid receptor. This may be the basis for ‘cross- talk’ between different nuclear receptors and their target genes. Although T3 receptors may bind as homodimers to the TREs, T3 effects on gene expression are usually mediated by T3 receptor/ RXR heterodimers.

Binding of the T3 receptor/ RXR heterodimer to TRE does not require T3 or 9- cis- retinoic acid, the ligand for RXR. The DBDs of these (and other) nuclear receptors contain two ‘zinc fingers’ (pep tide loops that chelate a zinc atom) that fit in the grooves of the DNA and are, thus, very important for the specificity of the receptor- promoter interaction. In the absence of T3 and irrespective of the presence of 9- cis- retinoic acid, binding of the T3 receptor/ RXR heterodimer to the TRE results in suppressed gene transcription mediated by the binding of corepressor proteins such as NCoR (nuclear corepressor) or SMRT (silencing mediator of retinoid and thyroid hormone receptors) to a specific region (CoR box) of the unliganded T3 receptor (Figure 2). These corepressors directly or indirectly inhibit the activity of the basal transcription machinery.

Fig2. Simplistic model of the regulation of gene transcription by T3 . RXR, retinoid X receptor; TR, T3 receptor; TRE, T3 response element in the promoter of a T3- responsive gene.

Binding of T3 induces a conformational change in the T3 receptor, which results in the release of the corepressors and the recruitment of coactivator proteins such as SRC1 (steroid receptor coactivator- 1) and CBP (cAMP response element- binding protein (CREB)- binding protein). The AF2 domain, a highly conserved 9- amino acid sequence located at the C- terminus of the different nuclear receptors, plays an important role in the binding of the coactivators. The latter directly or indirectly stimulate the activity of the basal transcription machinery. One mechanism by which transcription is stimulated involves the histone acetyltransferase activity of the coactivators or of other proteins with which they interact. Acetylation of histones loosens the chromatin structure and thus facilitates interaction of the transcription machinery with the DNA. Conversely, corepressors may recruit proteins with deacetylase activity.

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مواضيع ذات صلة

T3 Inhibition of TSH and TRH Gene Expression

Role of Thyroid Hormone in Thermogenesis

Metabolism of Thyroid Hormone :Deiodination

Thyroid Hormone Transporters

Ghrelin, Leptin, and Energy Use

Coordination of Gastroenteropancreatic Hormone Release

Pancreatic, Biliary, and Intestinal Secretions

Hormone-Secreting Cells: Their Distribution in the Gastroenteropancreatic Complex

Leptin Functions as a Satiety Factor

Glucagon and Glucagon-like Peptides— Biosynthesis and Secretion

Adult Growth Hormone Deficiency

Hypopituitary crisis