T3 receptor

Nonspecific immunosuppressive therapy in an adult patient is usually through cyclosporin (35), started intravenously at the time of transplantation, and given orally once feeding is tolerated. Typically, methylprednisone is started also at the time of transplantation, then reduced to a maintenance dose. A athioprine (31) may also be used in conjunction with the prednisone to achieve adequate immunosuppression. Whereas the objective of immunosuppression is to protect the transplant, general or excessive immunosuppression may lead to undesirable compHcations, eg, opportunistic infections and potential malignancies. These adverse effects could be avoided if selective immunosuppression could be achieved. Suspected rejection episodes are treated with intravenous corticosteroids. Steroid-resistant rejection may be treated with monoclonal antibodies (78,79) such as Muromonab-CD3, specific for the T3-receptor on human T-ceUs. Alternatively, antithymocyte globulin (ATG) may be used against both B- and T-ceUs. 

The adult brain is endowed with nuclear as well as cytosolic and membrane T3 receptors that have been visualized by autoradiography and studied biochemically [30-33]. Both neurons and neuropil are labeled by [ 1251]T3, and the labeling is selective across brain regions. Functionally, one of the most prominent features of neural action of thyroid hormone in adulthood is subsensitivity to norepinephrine as a result of a hypothyroid state [27], These changes may be reflections of loss of dendritic spines in at least some neurons of the adultbrain. Clinically, thyroid hormone deficiency increases the probability of depressive illness, whereas thyroid excess increases the probability of mania (Ch. 52) in susceptible individuals [27],... 

The thyroid releases predominantly thyroxine (T4). However, the active form appears to be triiodothyronine (T3) T4 is converted in part to T3, receptor affinity in target organs being 10-fold higher for T3. The effect of T3 develops more rapidly and has a shorter duration than does that of T4. Plasma elimination tip for T4 is about 7 d that for T3, however, is only 1.5 d. Conversion of T4 to T3 releases iodide 150 pg T4 contains 100 pg of iodine. 

The 5-H T3 receptor is the only monoamine receptor coupled to an ion channel, probably a Ca " channel. It is found in the cortex, hippocampus, and area postrema. It is typically localized presynaptically and regulates neurotransmitter release. Well-known antagonists are the potent antiemetics ondansetron and granisetron. 

A large number of proto-oncogenes code for transcription factors required for progression of the cell cycle and/or for the differentiation of the cell. The best known and investigated examples of oncogenic mutated transcription factors involve the jun, fos and myc genes and the genes for the T3 receptor and the vitamin A acid receptor. 

Possibly, the constitutive repression of target genes of the T3 receptor brings about a switch from a differentiation pathway to unprogrammed cell division. 

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. 

Model of the interaction of T3 with the T3 receptor. A Inactive phase —the unliganded T3 receptor dimer bound to the thyroid hormone response element (TRE) along with corepressors acts as a suppressor of gene transcription. B Active phase — T3 and T4... 

Thyroid hormone Synthesis of pumps a) Increased gene transcription (through direct interaction of nuclear T3-receptor complex with c/s-regulatory upstream gene element, or secondary to T3 induction of other proteins, or to altered ion fluxes) b) Posttranscriptional effects on mRNA levels c) Translational effects... 

Although the importance of the nuclear T3 receptor is well established, there also is evidence for the existence of non-nuclear T3 receptors. For example, Segal and Ingbar46 demonstrated an immediate T3-mediated increase in calcium accumulation in rat thymocytes, an increase that was insensitive to inhibitors of protein biosynthesis. A direct effect on oxidative phosphorylation has been suggested to result from T3 binding to saturable receptors of mitochondrial membranes. The possible roles of non-nuclear T3 receptors have been reviewed by Sterling47. 

Trioidothyronine from plasma, or that generated from T4 in the cells, may interact with specific cell receptors. However, there seems to be an equilibrium between the free and bound T3, and T3 penetrates the nuclear membrane without being bound to the cytoplasmic receptor protein. In the nucleus, however, T3 interacts with a chromatin-bound receptor and affects mRNA transcription. The responsiveness of various cells to T3 is correlated with the presence of nuclear T3 receptors. T3 receptors are also present in mitochondria 02 consumption by mitochondria is increased under the influence of T3. The function of cytosolic T3 receptors may be simply to concentrate T3 inside the cell rather than to serve as transporters. These processes are illustrated in Figure 16.15. 

Figure 16.15 Effect of triiodothyronine on cells. In the bloodstream, protein-bound triiodothyronine (P-T3) is in equilibrium with free T3. The latter penetrates cell membranes with ease and may be concentrated in the cytosol by a T3 binding protein (Rc). Free cytosolic T3, in equilibrium with Rc-T3, may interact with mitochondrial T3 receptors or may penetrate the nuclear membrane to interact with a T3 receptor on chromatin.

Brtko, J. and Filipcik, P., Effect of selenite and selenate on rat liver nuclear 3,5,3 -triiodothyronine (T3) receptor, Biol. Trace Element Res., 41, 191, 1994. 

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... 

For direct repeat HREs, the spacing of the two half-sites is often the decisive, if not the only, element based on which the receptor (homodimer or heterodimer) recognizes its own HRE and discriminates against related HREs. The solution of the structures of heterodimer-DNA complexes (review Steimetz et al., 2001) has shown how these receptors can distinguish between highly related HREs (Fig.4.7). As an example, the structure of a DNA-bound receptor-heterodimer composed of the DNA-binding domain of RXR and the T3-receptor (Rastinejad et al., 1995) is given in Fig. 4.7. 

Thyroid hormone binds to receptors in the nucleus that control the expression of genes responsible for many metabolic processes. The T3 receptor exists in two monomeric forms alpha and beta. When activated by T3, the a and (3 monomers combine to form ao, PP, or aP dimers. These Tj-activated dimers bind to DNA response elements and control the synthesis of RNA, which codes for specific proteins that mediate the actions of thyroid hormones. 

Immunomodulatory, Immunosuppressant. Purified murine (mouse) mAb, directed against CD3 (T3) receptor on the surface of T lymphocytes. Cultured from murine ascites. 93% monomeric IgG2a. 

An additional tool in structural analysis and analogue design has been TTR (formerly called T4 binding prealbumin), a plasma protein that binds as much as 27% of plasma T3 (107). The amino acid sequence of the TTR T3 binding site is known, and the protein has therefore served as a model, although admittedly an approximate model, for the T3 receptor. The TTR model portrays the T3 molecule as placed in an envelope... 

One result of these unique features of T3 metabolism in brain is shown in Table 3. If vivo saturation techniques are used to determine the binding capacity of the T3 receptors in cerebral cortex, a much lower maximal binding capacity is calculated than is the case vitro (5,31). This is not the case in liver where the results of binding... 

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