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Research ArticleSpecial Issue IUPHAR Compendium of the Pharmacology and Classification of the Nuclear Receptor Superfamily 2006

International Union of Pharmacology. LIX. The Pharmacology and Classification of the Nuclear Receptor Superfamily: Thyroid Hormone Receptors

Frédéric Flamant, John D. Baxter, Douglas Forrest, Samuel Refetoff, Herbert Samuels, Tom S. Scanlan, Bjorn Vennström and Jacques Samarut
Pharmacological Reviews December 2006, 58 (4) 705-711; DOI: https://doi.org/10.1124/pr.58.4.3
Frédéric Flamant
Laboratoire de Biologie Moléculaire et Cellulaire de l'Ecole Normale Supérieure de Lyon, Unité Mixte de Recherche, Centre National de la Recherche Scientifique 5665, Laboratoire Associé Institut National de la Recherche Agronomique 913, l'Institut Fédératif de Recherches 128, Lyon, France (F.F., J.S.); Diabetes Center and Department of Medicine (J.D.B.), and Program in Chemistry and Chemical Biology, Department of Pharmaceutical Chemistry (T.S.S.), University of California, San Francisco, San Francisco, California; Clinical Endocrinology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (D.F.); Departments of Medicine Pediatrics, The University of Chicago, Chicago, Illinois (S.R.); Departments of Pharmacology and Medicine, New York University School of Medicine, New York, New York (H.S.); and Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden (B.V.)
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John D. Baxter
Laboratoire de Biologie Moléculaire et Cellulaire de l'Ecole Normale Supérieure de Lyon, Unité Mixte de Recherche, Centre National de la Recherche Scientifique 5665, Laboratoire Associé Institut National de la Recherche Agronomique 913, l'Institut Fédératif de Recherches 128, Lyon, France (F.F., J.S.); Diabetes Center and Department of Medicine (J.D.B.), and Program in Chemistry and Chemical Biology, Department of Pharmaceutical Chemistry (T.S.S.), University of California, San Francisco, San Francisco, California; Clinical Endocrinology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (D.F.); Departments of Medicine Pediatrics, The University of Chicago, Chicago, Illinois (S.R.); Departments of Pharmacology and Medicine, New York University School of Medicine, New York, New York (H.S.); and Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden (B.V.)
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Douglas Forrest
Laboratoire de Biologie Moléculaire et Cellulaire de l'Ecole Normale Supérieure de Lyon, Unité Mixte de Recherche, Centre National de la Recherche Scientifique 5665, Laboratoire Associé Institut National de la Recherche Agronomique 913, l'Institut Fédératif de Recherches 128, Lyon, France (F.F., J.S.); Diabetes Center and Department of Medicine (J.D.B.), and Program in Chemistry and Chemical Biology, Department of Pharmaceutical Chemistry (T.S.S.), University of California, San Francisco, San Francisco, California; Clinical Endocrinology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (D.F.); Departments of Medicine Pediatrics, The University of Chicago, Chicago, Illinois (S.R.); Departments of Pharmacology and Medicine, New York University School of Medicine, New York, New York (H.S.); and Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden (B.V.)
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Samuel Refetoff
Laboratoire de Biologie Moléculaire et Cellulaire de l'Ecole Normale Supérieure de Lyon, Unité Mixte de Recherche, Centre National de la Recherche Scientifique 5665, Laboratoire Associé Institut National de la Recherche Agronomique 913, l'Institut Fédératif de Recherches 128, Lyon, France (F.F., J.S.); Diabetes Center and Department of Medicine (J.D.B.), and Program in Chemistry and Chemical Biology, Department of Pharmaceutical Chemistry (T.S.S.), University of California, San Francisco, San Francisco, California; Clinical Endocrinology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (D.F.); Departments of Medicine Pediatrics, The University of Chicago, Chicago, Illinois (S.R.); Departments of Pharmacology and Medicine, New York University School of Medicine, New York, New York (H.S.); and Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden (B.V.)
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Herbert Samuels
Laboratoire de Biologie Moléculaire et Cellulaire de l'Ecole Normale Supérieure de Lyon, Unité Mixte de Recherche, Centre National de la Recherche Scientifique 5665, Laboratoire Associé Institut National de la Recherche Agronomique 913, l'Institut Fédératif de Recherches 128, Lyon, France (F.F., J.S.); Diabetes Center and Department of Medicine (J.D.B.), and Program in Chemistry and Chemical Biology, Department of Pharmaceutical Chemistry (T.S.S.), University of California, San Francisco, San Francisco, California; Clinical Endocrinology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (D.F.); Departments of Medicine Pediatrics, The University of Chicago, Chicago, Illinois (S.R.); Departments of Pharmacology and Medicine, New York University School of Medicine, New York, New York (H.S.); and Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden (B.V.)
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Tom S. Scanlan
Laboratoire de Biologie Moléculaire et Cellulaire de l'Ecole Normale Supérieure de Lyon, Unité Mixte de Recherche, Centre National de la Recherche Scientifique 5665, Laboratoire Associé Institut National de la Recherche Agronomique 913, l'Institut Fédératif de Recherches 128, Lyon, France (F.F., J.S.); Diabetes Center and Department of Medicine (J.D.B.), and Program in Chemistry and Chemical Biology, Department of Pharmaceutical Chemistry (T.S.S.), University of California, San Francisco, San Francisco, California; Clinical Endocrinology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (D.F.); Departments of Medicine Pediatrics, The University of Chicago, Chicago, Illinois (S.R.); Departments of Pharmacology and Medicine, New York University School of Medicine, New York, New York (H.S.); and Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden (B.V.)
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Bjorn Vennström
Laboratoire de Biologie Moléculaire et Cellulaire de l'Ecole Normale Supérieure de Lyon, Unité Mixte de Recherche, Centre National de la Recherche Scientifique 5665, Laboratoire Associé Institut National de la Recherche Agronomique 913, l'Institut Fédératif de Recherches 128, Lyon, France (F.F., J.S.); Diabetes Center and Department of Medicine (J.D.B.), and Program in Chemistry and Chemical Biology, Department of Pharmaceutical Chemistry (T.S.S.), University of California, San Francisco, San Francisco, California; Clinical Endocrinology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (D.F.); Departments of Medicine Pediatrics, The University of Chicago, Chicago, Illinois (S.R.); Departments of Pharmacology and Medicine, New York University School of Medicine, New York, New York (H.S.); and Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden (B.V.)
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Jacques Samarut
Laboratoire de Biologie Moléculaire et Cellulaire de l'Ecole Normale Supérieure de Lyon, Unité Mixte de Recherche, Centre National de la Recherche Scientifique 5665, Laboratoire Associé Institut National de la Recherche Agronomique 913, l'Institut Fédératif de Recherches 128, Lyon, France (F.F., J.S.); Diabetes Center and Department of Medicine (J.D.B.), and Program in Chemistry and Chemical Biology, Department of Pharmaceutical Chemistry (T.S.S.), University of California, San Francisco, San Francisco, California; Clinical Endocrinology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (D.F.); Departments of Medicine Pediatrics, The University of Chicago, Chicago, Illinois (S.R.); Departments of Pharmacology and Medicine, New York University School of Medicine, New York, New York (H.S.); and Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden (B.V.)
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Introduction

The initial identification of thyroid hormone receptors (TRs1) was based on binding studies (Oppenheimer et al., 1972). The TR main ligand is 3,5,3′-triiodo-l-thyronine (T3). T3 production primarily results from deiodination of thyroxine (T4), which is secreted by the thyroid gland. Most metabolites of T4 and T3 are poor TR ligands except for 3,3′,5-triiodo-thyroacetic acid (TRIAC), which is present at very low levels. TRs are encoded by the THRA (NR1A1) and THRB (NR1A2) genes. The THRA gene was originally identified in chicken as the cellular homolog of the v-erbA oncogene (Sap et al., 1986). THRB was also cloned by low-stringency screening with the same probe of human and rat cDNA libraries (Weinberger et al., 1986; Thompson et al., 1987). Although mRNA and protein abundance is variable, THRA is ubiquitously expressed. THRB expression pattern is more restricted and is developmentally regulated. Its main expression sites are the liver, pituitary, inner ear, retina, and several brain areas. The THRA promoter possesses a response element for the estrogen receptor-related-α (NR3B1) orphan receptor (Vanacker et al., 1998), and the 3′-end overlaps at its RevErbAα (NR1D1)-encoding gene, which is transcribed from the antisense DNA strand. The consequences of these features on THRA regulation are unclear, although the 3′-end overlap might explain the moderate diurnal variations of TRα2 isoform protein level observed in the liver (Zandieh-Doulabi et al., 2003). THRA and THRB encode the major receptor isoforms TRα1, TRβ1, and TRβ2 [the TRβ3 receptor (Williams, 2000) is apparently rat-specific], as well as several isoforms unable to bind any ligand (TRα2, TRα3, TRΔα1, TRΔα2, and the rat-specific TRΔβ3). TRα2 and TRα3 mRNA results from alternate splicing and differs from TRα1 at their C terminus. TRΔα1 and TRΔα2 are truncated versions of TRα1 and TRα2, respectively, and are translated from mRNA initiated from an internal promoter present in intron 7. In transfected cells, all of these isoforms prevent the T3-induced transcriptional activation mediated by the T3-binding isoforms, but the underlying mechanisms are poorly understood. Alternative translation initiations on the TRα1 mRNA still provide other isoforms (Bigler et al., 1992). One of these isoforms, p43, has been proposed to be a mitochondrial receptor that regulates mitochondrial transcription (Casas et al., 1999). In vitro data indicate that TR acts mainly as heterodimers with RXR, although TRβ1 homodimers and TR/retinoic acid receptor heterodimers can form (Forman et al., 1992; Lee and Privalsky, 2005). DNA binding of TR/RXR heterodimers is not ligand-dependent and is efficient on DR-4 elements (5′-AGGTCANNNNAGGTCA-3′) and inverted palindromes. Although it has been thought that RXR in the TR/RXR heterodimer could not bind its cognate ligand, more recent studies indicate that at least in some cases the RXR ligand 9-cis retinoic acid can influence the activity of the TR/RXR heterodimer (Li et al., 2002) (Castillo et al., 2004; Li et al., 2004).

Structure

X-ray crystallography revealed the structure of the TR ligand-binding domain bound to agonist (Wagner et al., 2001; Borngraeber et al., 2003; Nunes et al., 2004). These data suggest that upon T3 binding the C-terminal helix 12 folds into the scaffold formed by helix 3,4,5, creating a surface with a hydrophobic cleft suitable for coactivator interaction (Feng et al., 1998; Ribeiro et al., 1998) and preventing corepressor interaction (Marimuthu et al., 2002). The structure of TR/RXR DNA-binding domains bound to a DR-4 element also demonstrate that this spacing between the two binding sites is suitable for optimal RXR/TR dimerization (Rastinejad et al., 1995).

Target Genes

The probably large repertoire of TR target genes remains to be clearly defined. The demonstration that a given gene is directly regulated by TR requires the convergent accumulation of several experimental evidences. Increasing or decreasing T3 levels in cultured cells or living animals should change the mRNA steadystate level T3 regulation and should also be observed in a transient expression assay using an artificial construct, where a fragment of the putative target gene is introduced. The T3 response element(s) present in this DNA fragment should be precisely mapped by deletion analysis. In vitro protein interaction studies should identify the TR-binding site present on this fragment. Finally, it will soon be requested to demonstrate by chromatin immunoprecipitation the actual occupancy by TR of the region containing the T3 response element in a chromosomal context. Very few genes fulfill all the criteria to be considered direct TR targets. The best-known TR target genes encode type 1 deiodinase in liver (Koenig, 2005) and the basic transcription element-binding protein (Morita et al., 2003), Hairless corepressor (Thompson, 1996), and neurogranin (Guadano-Ferraz et al., 1997; Morte et al., 1997) in brain. Recent microarray analyses identified many new putative candidates in liver (Flores-Morales et al., 2002; Yen et al., 2003). Surprisingly, many are down-regulated by T3. For most of these genes, bioinformatics methods did not reveal the presence of consensus DR-4 elements, raising doubts on a direct regulation of these genes by TR. The coming years will tell whether the gap between the microarray data and previous in vitro data can be filled or whether the diversity of TR-mediated regulation has been underestimated.

Pharmacology

T4 and T3 treatment has several potentially beneficial effects, including the lowering of body weight and plasma cholesterol level; however, an excess of T3 provokes bone and muscle loss and a dangerous tachycardia and can lead to atrial arrhythmia. These adverse effects largely counterbalance the possible benefits. One would expect that TR agonists or antagonists would be of great interest if they could act in an isotype isoform or tissue-specific manner. Because T3 is unrelated to all known ligands for other nuclear receptors, T3 analogs might also act on TR without interfering with the ligand domain of other nuclear receptors. It should be kept in mind, however, that at least in cultured cells T3 and related compounds display a TR-independent activity called nongenomic activity (Davis et al., 2005). GC-1 and KB-141 are the most promising available compounds because they are almost specific for TRβ. In animal models, they were found to decrease plasma cholesterol and triglycerides levels and induce fat loss without a visible effect on heart and muscle (Grover et al., 2003; Baxter et al., 2004). Clinical trials are underway for other ligands from the KB series designed by KaroBio with similar properties. Finally, compounds that can rescue functionally impaired TRβ receptors may provide new strategies for the treatment of resistance to thyroid hormone (RTH; see “Pathology”) (Koh and Biggins, 2005).

Currently, there is no true high-affinity antagonist available for TR (Schapira et al., 2003). The mode of action of the widely used antiarrhythmic drug amiodarone is unclear. Its main metabolite desethylamiodarone is thought to be a weak competitive ligand of T3 for TRα1 but not for TRβ1. A noncompetitive binding site is postulated to be on the outside surface of the TRβ1 receptor, overlapping the regions where coactivator and corepressor bind. Amiodarone treatment would act by preventing the recruitment of coactivators by TRβ1 (van Beeren et al., 1995, 1996, 2000, 2003). The NH3 compound acts as a relatively specific antagonist; its binding places the TRα1 receptor in a neutral conformation that does not permit either coactivator or corepressor recruitment (Nguyen et al., 2002, 2005). Other ligands discovered after high throughput screening or in silico virtual screening are currently being evaluated. O-Alkyl derivatives of T3 have been synthesized with the aim of stabilizing a nonproductive conformation of key residues in the ligand-binding pocket and thus disfavoring the equilibrium to the agonist conformation of helix-12. Some induce a stabilization of an inactive conformation and lead to an “indirect antagonism” (Hedfors et al., 2005). It has been shown recently that the deamination of some β-aminoketones produce reactive unsaturated ketones that covalently bind to TR, inhibiting TR-coactivator interaction and suppressing its transcriptional activity (Arnold et al., 2005).

Pathology

T3 exerts a pleiotropic effect on development and homeostasis (Yen, 2001). Circulating levels of T4 and T3 in adults are usually very stable. Hyperthyroidism, often a consequence of Graves' disease, can result in goiter, periorbital edema, weight loss, tachycardia, palpitations, muscle weakness, osteoporosis, (especially in post-menopausal women), and mood disorders. Common signs of hypothyroidism are goiter, myxedema, fatigue, cold-intolerance, thinning hair, depression, dry skin, constipation, and bradycardia. If untreated, fetal and neonatal hypothyroidism also limit bone growth and are responsible for deafness and an irreversible mental retardation called cretinism. Thyroid-related pathology is largely avoidable in developed countries with established neonatal screening for abnormalities in thyroid hormone levels. However, there is growing concern that chemical substances present in food and in the environment might act as thyroid hormone disruptors that alter the circulating levels of T3 and TSH. The permanent exposure to such substances would favor the onset of a number of pathologies and would be harmful for pre- and postnatal brain development (Aoki, 2001; Zoeller et al., 2002). These substances include polychlorinated biphenyls (Zoeller et al., 2000; Gauger et al., 2004), bisphenol A and related compounds (Zoeller et al., 2005), and dioxin and dioxin-like compounds (Nishimura et al., 2003; Viluksela et al., 2004; Yamada-Okabe et al., 2004). The underlying mechanisms are very complex and poorly understood. It seems that some of these molecules act as weak TR ligands (Moriyama et al., 2002; Kitamura et al., 2005).

Human germline mutations are known for THRB but not for THRA, suggesting that THRA mutations might be either lethal or related to unexpected clinical features. THRB mutations cause a dominant and polymorphic genetic disease known as RTH (Weiss and Refetoff, 2000; Yen, 2003). Many mutations have been reported that fall into three clusters located in the ligand-binding domain: AA234-282, 310-353, and 429-461 (Collingwood et al., 1998). Almost all of these mutations compromise ligand-binding coactivator recruitment or corepressor release. High levels of T4 and T3 without TSH suppression are typically observed. Inheritance of RTH is dominant since mutant TRβ1 and TRβ2 interfere in a dominant-negative fashion, with the function of wild-type TRβ receptors altering feedback regulation on pituitary TSH secretion. Elevated circulating levels of T4 and T3 can create a condition that resembles hyperthyroidism in tissues that mainly express THRA. For example, tachycardia may be due to hyperthyroidism in the heart, where cardiomyocytes mainly express THRA. The condition is closer to hypothyroidism in tissues that express the mutated THRB allele, such as the liver.

Mouse Genetics

A collection of seven mutant alleles for THRA and nine mutant alleles for THRB that carry either knockout or knockin mutations have been generated over the last 10 years (Forrest and Vennstrom, 2000; Flamant and Samarut, 2003; Wondisford, 2003), and the collection is still growing. Although the diversity of phenotypes is confusing, at first glance the analysis provides a deeper view on TR function in vivo. The following summary conclusions can be drawn.

TRα1 is a main regulator of development in some tissues during the first weeks of postnatal preweaning development. These 3 weeks are characterized by a peak of circulating T3 and present some analogies with amphibian metamorphosis. As this point, T3 regulates intestinal remodeling (Plateroti et al., 2001), cerebellum development (Morte et al., 2002), spleen erythropoiesis (Angelin-Duclos et al., 2005), and bone growth (Bassett and Williams, 2003), mainly by activating TRα1. TRα1 also has a major role in setting cardiac function and thermogenesis (Wikstrom et al., 1998).

TRβ1 is the main isoform that regulates liver function and the development of hearing, and together with TRβ2, it has a major role in the feedback regulation of the hypothalamic-pituitary-thyroid axis (Forrest et al., 1996a,b). TRβ2 has a specific role in the differentiation of retinal cone photoreceptors required for color vision. TRβ2 also cooperates with TRβ1 in the feedback regulation for the hypothalamic-pituitary-thyroid axis. It may also be involved in the auditory system, but this role can be substituted by TRβ1, which is coexpressed with TRβ2 in the cochlea (Abel et al., 2001; Ng et al., 2001).

Unliganded TRα1 can regulate gene expression. This function is mainly evidenced by the fact that knocking out THRA or both THRA/THRB is less detrimental to development than either hypothyroidism (Flamant et al., 2002) or dominant-negative knockin THRA mutations (Tinnikov et al., 2002; Liu et al., 2003). Although the possibility for a nongenomic action of T3 should also be considered, these data support the idea that recruitment of corepressor on T3 target genes by unliganded TRα1 is detrimental to the development of hypothyroid animals. Due to uneven T3 distribution (Quignodon et al., 2004), unliganded TRα1 might be present in some tissues— even in nonpathological situations. It has been shown to repress cardiac gene expression in fetuses in euthyroid situation (Mai et al., 2004).

The contributions of TRα1, TRβ1, and TRβ2 to T3 action on a given tissue usually parallels their respective abundance. For example, the liver mainly expresses TRβ1, and microarray data indicate that the THRB knockout has a much more visible effect than THRA knockout on liver response to T3 (Yen et al., 2003). This difference suggests that, at least at first sight, TR functions are equal and redundant in tissues where they are simultaneously present.

Noncoding isoforms seem to modulate TR function. As discussed previously (Flamant and Samarut, 2003), this function is not clear for TRα2 but very likely for TRΔα1 and/or TRΔα2. The underlying mechanisms remain poorly understood (Gauthier et al., 2001).

Phenotypic analyses have been performed extensively, and a complete description would go beyond the scope of this review since it seems that every aspect of physiology and postnatal development can be influenced by T3 and TR. The main difficulty of these analyses is to unravel the cell-autonomous consequences of mutations from indirect effects. For example, THRB is expressed in the cerebellum only in Purkinje cells, but a THRB knockin mutation affects the proliferation of the neighboring granular cells, suggesting that T3 exerts part of its effect on granular cells indirectly by activating the secretion of trophic factors by Purkinje cells (Hashimoto et al., 2001). The CRE/loxP recombination strategy will certainly provide a new impetus to these studies by allowing for a spatial and temporal control of gene mutations. Some discrepancies also suggest that we are far from a complete understanding of TR action in vivo. For example, two knockin mutations of THRA have been made that are a priori-equivalent, but only one of these leads to obesity (Tinnikov et al., 2002; Liu et al., 2003). All of these observations suggest that THRA- and THRB-somatic and -germline mutations might be involved in a much larger number of human pathological conditions, including cancer (Cheng, 2003), than it is usually assumed and that new TR ligands will find many applications.

Tables 1 and 2 describe the major molecular, physiological, and pharmacological properties of TRα and TRβ, respectively.

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TABLE 1

TRα

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TABLE 2

TRβ

Acknowledgments

F.F. and J.S. are supported by the French Ministry of Research (Action Concertée Incitative Biologie Cellulaire Moléculaire et Structurale), Ligue Contre le Cancer (Équipe Labelisée), and the CASCADE European Network of Excellence (European Union contract no. FOOD-CT-2004-506319). D.F. is supported by the National Institutes of Health/National Institute on Deafness and Other Communication Disorders, a Hirschl Award, and the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases intramural research program.

Footnotes

  • ↵1 Abbreviations: TR, thyroid hormone receptor; T3, 3,5,3′-triiodo-l-thyronine; T4, thyroxine; TRIAC, 3,3′,5-triiodo-thyroacetic acid; RXR, retinoid X receptor; DR, direct repeat; RTH, resistance to thyroid hormone; TSH, thyroid-stimulating hormone.

  • Article, publication date, and citation information can be found at http://pharmrev.aspetjournals.org.

  • doi:10.1124/pr.58.4.3.

  • The American Society for Pharmacology and Experimental Therapeutics

References

  1. ↵
    Abel ED, Ahima RS, Boers ME, Elmquist JK, and Wondisford FE (2001) Critical role for thyroid hormone receptor beta2 in the regulation of paraventricular thyrotropin-releasing hormone neurons. J Clin Investig 107: 1017-1023.
    OpenUrlCrossRefPubMed
  2. ↵
    Angelin-Duclos C, Domenget C, Kolbus A, Beug H, Jurdic P, and Samarut J (2005) Thyroid hormone T3 acting through the thyroid hormone alpha receptor is necessary for implementation of erythropoiesis in the neonatal spleen environment in the mouse. Development 132: 925-934.
    OpenUrlAbstract/FREE Full Text
  3. ↵
    Aoki Y (2001) Polychlorinated biphenyls polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans as endocrine disrupters-what we have learned from Yusho disease. Environ Res 86: 2-11.
    OpenUrlPubMed
  4. ↵
    Arnold LA, Estebanez-Perpina E, Togashi M, Jouravel N, Shelat A, McReynolds AC, Mar E, Nguyen P, Baxter JD, Fletterick RJ, et al. (2005) Discovery of small molecule inhibitors of the interaction of thyroid hormone receptor with transcriptional coregulators. J Biol Chem 280: 43048-43055.
    OpenUrlAbstract/FREE Full Text
  5. ↵
    Bassett JH and Williams GR (2003) The molecular actions of thyroid hormone in bone. Trends Endocrinol Metab 14: 356-364.
    OpenUrlCrossRefPubMed
  6. ↵
    Baxter JD, Webb P, Grover G, and Scanlan TS (2004) Selective activation of thyroid hormone signaling pathways by GC-1: a new approach to controlling cholesterol and body weight. Trends Endocrinol Metab 15: 154-157.
    OpenUrlCrossRefPubMed
  7. ↵
    Bigler J, Hokanson W, and Eisenman RN (1992) Thyroid hormone receptor transcriptional activity is potentially autoregulated by truncated forms of the receptor. Mol Cell Biol 12: 2406-2417.
    OpenUrlAbstract/FREE Full Text
  8. ↵
    Borngraeber S, Budny MJ, Chiellini G, Cunha-Lima ST, Togashi M, Webb P, Baxter JD, Scanlan TS, and Fletterick RJ (2003) Ligand selectivity by seeking hydrophobicity in thyroid hormone receptor. Proc Natl Acad Sci USA 100: 15358-15363.
    OpenUrlAbstract/FREE Full Text
  9. ↵
    Casas F, Rochard P, Rodier A, Cassar-Malek I, Marchal-Victorion S, Wiesner RJ, Cabello G, and Wrutniak C (1999) A variant form of the nuclear triiodothyronine receptor c-ErbAalpha1 plays a direct role in regulation of mitochondrial RNA synthesis. Mol Cell Biol 19: 7913-7924.
    OpenUrlAbstract/FREE Full Text
  10. ↵
    Castillo AI, Sanchez-Martinez R, Moreno JL, Martinez-Iglesias OA, Palacios D, and Aranda A (2004) A permissive retinoid X receptor/thyroid hormone receptor heterodimer allows stimulation of prolactin gene transcription by thyroid hormone and 9-cis-retinoic acid. Mol Cell Biol 24: 502-513.
    OpenUrlAbstract/FREE Full Text
  11. ↵
    Cheng SY (2003) Thyroid hormone receptor mutations in cancer. Mol Cell Endocrinol 213: 23-30.
    OpenUrlCrossRefPubMed
  12. ↵
    Collingwood TN, Wagner R, Matthews CH, Clifton-Bligh RJ, Gurnell M, Rajanayagam O, Agostini M, Fletterick RJ, Beck-Peccoz P, Reinhardt W, et al. (1998) A role for helix 3 of the TRbeta ligand-binding domain in coactivator recruitment identified by characterization of a third cluster of mutations in resistance to thyroid hormone. EMBO (Eur Mol Biol Organ) J 17: 4760-4770.
    OpenUrlAbstract
  13. ↵
    Davis PJ, Davis FB, and Cody V (2005) Membrane receptors mediating thyroid hormone action. Trends Endocrinol Metab 16: 429-435.
    OpenUrlCrossRefPubMed
  14. ↵
    Feng W, Ribeiro RC, Wagner RL, Nguyen H, Apriletti JW, Fletterick RJ, Baxter JD, Kushner PJ, and West BL (1998) Hormone-dependent coactivator binding to a hydrophobic cleft on nuclear receptors. Science (Wash DC) 280: 1747-1749.
    OpenUrlAbstract/FREE Full Text
  15. ↵
    Flamant F, Poguet AL, Plateroti M, Chassande O, Gauthier K, Streichenberger N, Mansouri A, and Samarut J (2002) Congenital hypothyroid Pax8(-/-) mutant mice can be rescued by inactivating the TRalpha gene. Mol Endocrinol 16: 24-32.
    OpenUrlCrossRefPubMed
  16. ↵
    Flamant F and Samarut J (2003) Thyroid hormone receptors: lessons from knockout and knock-in mutant mice. Trends Endocrinol Metab 14: 85-90.
    OpenUrlCrossRefPubMed
  17. ↵
    Flores-Morales A, Gullberg H, Fernandez L, Stahlberg N, Lee NH, Vennstrom B, and Norstedt G (2002) Patterns of liver gene expression governed by TRbeta. Mol Endocrinol 16: 1257-1268.
    OpenUrlCrossRefPubMed
  18. ↵
    Forman BM, Casanova J, Raaka BM, Ghysdael J, and Samuels HH (1992) Half-site spacing and orientation determines whether thyroid hormone and retinoic acid receptors and related factors bind to DNA response elements as monomers homodimers or heterodimers. Mol Endocrinol 6: 429-442.
    OpenUrlCrossRefPubMed
  19. ↵
    Forrest D, Erway LC, Ng L, Altschuler R, and Curran T (1996a) Thyroid hormone receptor beta is essential for development of auditory function. Nat Genet 13: 354-357.
    OpenUrlCrossRefPubMed
  20. ↵
    Forrest D, Hanebuth E, Smeyne RJ, Everds N, Stewart CL, Wehner JM, and Curran T (1996b) Recessive resistance to thyroid hormone in mice lacking thyroid hormone receptor beta: evidence for tissue-specific modulation of receptor function. EMBO (Eur Mol Biol Organ) J 15: 3006-3015.
    OpenUrlPubMed
  21. ↵
    Forrest D and Vennstrom B (2000) Functions of thyroid hormone receptors in mice Thyroid 10: 41-52.
    OpenUrlCrossRefPubMed
  22. ↵
    Gauger KJ, Kato Y, Haraguchi K, Lehmler HJ, Robertson LW, Bansal R, and Zoeller RT (2004) Polychlorinated biphenyls (PCBs) exert thyroid hormone-like effects in the fetal rat brain but do not bind to thyroid hormone receptors. Environ Health Perspect 112: 516-523.
    OpenUrlPubMed
  23. ↵
    Gauthier K, Plateroti M, Harvey CB, Williams GR, Weiss RE, Refetoff S, Willott JF, Sundin V, Roux JP, Malaval L, et al. (2001) Genetic analysis reveals different functions for the products of the thyroid hormone receptor alpha locus. Mol Cell Biol 21: 4748-4760.
    OpenUrlAbstract/FREE Full Text
  24. ↵
    Grover GJ, Mellstrom K, Ye L, Malm J, Li YL, Bladh LG, Sleph PG, Smith MA, George R, Vennstrom B, et al. (2003) Selective thyroid hormone receptor-beta activation: a strategy for reduction of weight cholesterol and lipoprotein (a) with reduced cardiovascular liability. Proc Natl Acad Sci USA 100: 10067-10072.
    OpenUrlAbstract/FREE Full Text
  25. ↵
    Guadano-Ferraz A, Escamez MJ, Morte B, Vargiu P, and Bernal J (1997) Transcriptional induction of RC3/neurogranin by thyroid hormone: differential neuronal sensitivity is not correlated with thyroid hormone receptor distribution in the brain. Brain Res Mol Brain Res 49: 37-44.
    OpenUrlPubMed
  26. ↵
    Hashimoto K, Curty FH, Borges PP, Lee CE, Abel ED, Elmquist JK, Cohen RN, and Wondisford FE (2001) An unliganded thyroid hormone receptor causes severe neurological dysfunction. Proc Natl Acad Sci USA 98: 3998-4003.
    OpenUrlAbstract/FREE Full Text
  27. ↵
    Hedfors A, Appelqvist T, Carlsson B, Bladh LG, Litten C, Agback P, Grynfarb M, Koehler KF, and Malm J (2005) Thyroid receptor ligands. 3. Design and synthesis of 3,5-dihalo-4-alkoxyphenylalkanoic acids as indirect antagonists of the thyroid hormone receptor. J Med Chem 48: 3114-3117.
    OpenUrlCrossRefPubMed
  28. ↵
    Kitamura S, Kato T, Iida M, Jinno N, Suzuki T, Ohta S, Fujimoto N, Hanada H, Kashiwagi K, and Kashiwagi A (2005) Anti-thyroid hormonal activity of tetrabromobisphenol A, a flame retardant, and related compounds: affinity to the mammalian thyroid hormone receptor and effect on tadpole metamorphosis. Life Sci 76: 1589-1601.
    OpenUrlCrossRefPubMed
  29. ↵
    Koenig RJ (2005) Regulation of type 1 iodothyronine deiodinase in health and disease. Thyroid 15: 835-840.
    OpenUrlCrossRefPubMed
  30. ↵
    Koh JT and Biggins JB (2005) Ligand-receptor engineering and its application towards the complementation of genetic disease and target identification. Curr Top Med Chem 5: 413-420.
    OpenUrlCrossRefPubMed
  31. ↵
    Lee S and Privalsky ML (2005) Heterodimers of retinoic acid receptors and thyroid hormone receptors display unique combinatorial regulatory properties. Mol Endocrinol 19: 863-878.
    OpenUrlCrossRefPubMed
  32. ↵
    Li D, Li T, Wang F, Tian H, and Samuels HH (2002) Functional evidence for retinoid X receptor (RXR) as a nonsilent partner in the thyroid hormone receptor/RXR heterodimer. Mol Cell Biol 22: 5782-5792.
    OpenUrlAbstract/FREE Full Text
  33. ↵
    Li D, Yamada T, Wang F, Vulin AI, and Samuels HH (2004) Novel roles of retinoid X receptor (RXR) and RXR ligand in dynamically modulating the activity of the thyroid hormone receptor/RXR heterodimer. J Biol Chem 279: 7427-7437.
    OpenUrlAbstract/FREE Full Text
  34. ↵
    Liu YY, Schultz JJ, and Brent GA (2003) A thyroid hormone receptor alpha gene mutation (P398H) is associated with visceral adiposity and impaired catecholamine-stimulated lipolysis in mice. J Biol Chem 278: 38913-38920.
    OpenUrlAbstract/FREE Full Text
  35. ↵
    Mai W, Janier MF, Allioli N, Quignodon L, Chuzel T, Flamant F, and Samarut J (2004) Thyroid hormone receptor alpha is a molecular switch of cardiac function between fetal and postnatal life. Proc Natl Acad Sci USA 101: 10332-10337.
    OpenUrlAbstract/FREE Full Text
  36. ↵
    Marimuthu A, Feng W, Tagami T, Nguyen H, Jameson JL, Fletterick RJ, Baxter JD, and West BL (2002) TR surfaces and conformations required to bind nuclear receptor corepressor. Mol Endocrinol 16: 271-286.
    OpenUrlCrossRefPubMed
  37. ↵
    Morita M, Kobayashi A, Yamashita T, Shimanuki T, Nakajima O, Takahashi S, Ikegami S, Inokuchi K, Yamashita K, Yamamoto M, et al. (2003) Functional analysis of basic transcription element binding protein by gene targeting technology. Mol Cell Biol 23: 2489-2500.
    OpenUrlAbstract/FREE Full Text
  38. ↵
    Moriyama K, Tagami T, Akamizu T, Usui T, Saijo M, Kanamoto N, Hataya Y, Shimatsu A, Kuzuya H, and Nakao K (2002) Thyroid hormone action is disrupted by bisphenol A as an antagonist. J Clin Endocrinol Metab 87: 5185-5190.
    OpenUrlCrossRefPubMed
  39. ↵
    Morte B, Iniguez MA, Lorenzo PI, and Bernal J (1997) Thyroid hormone-regulated expression of RC3/neurogranin in the immortalized hypothalamic cell line GT1-7. J Neurochem 69: 902-909.
    OpenUrlPubMed
  40. ↵
    Morte B, Manzano J, Scanlan T, Vennstrom B, and Bernal J (2002) Deletion of the thyroid hormone receptor alpha 1 prevents the structural alterations of the cerebellum induced by hypothyroidism. Proc Natl Acad Sci USA 99: 3985-3989.
    OpenUrlAbstract/FREE Full Text
  41. ↵
    Ng L, Hurley JB, Dierks B, Srinivas M, Salto C, Vennstrom B, Reh TA, and Forrest D (2001) A thyroid hormone receptor that is required for the development of green cone photoreceptors. Nat Genet 27: 94-98.
    OpenUrlCrossRefPubMed
  42. ↵
    Nguyen NH, Apriletti JW, Baxter JD, and Scanlan TS (2005) Hammett analysis of selective thyroid hormone receptor modulators reveals structural and electronic requirements for hormone antagonists. J Am Chem Soc 127: 4599-4608.
    OpenUrlCrossRefPubMed
  43. ↵
    Nguyen NH, Apriletti JW, Cunha Lima ST, Webb P, Baxter JD, and Scanlan TS (2002) Rational design and synthesis of a novel thyroid hormone antagonist that blocks coactivator recruitment. J Med Chem 45: 3310-3320.
    OpenUrlCrossRefPubMed
  44. ↵
    Nishimura N, Yonemoto J, Miyabara Y, Sato M, and Tohyama C (2003) Rat thyroid hyperplasia induced by gestational and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Endocrinology 144: 2075-2083.
    OpenUrlCrossRefPubMed
  45. ↵
    Nunes FM, Aparicio R, Santos MA, Portugal RV, Dias SM, Neves FA, Simeoni LA, Baxter JD, Webb P, and Polikarpov I (2004) Crystallization and preliminary X-ray diffraction studies of isoform alpha1 of the human thyroid hormone receptor ligand-binding domain. Acta Crystallogr D Biol Crystallogr 60: 1867-1870.
    OpenUrlCrossRefPubMed
  46. ↵
    Oppenheimer JH, Koerner K, Schwartz HL, and Surks MI (1972) Specific nuclear triiodothyronine binding sites in rat liver and kidney. J Clin Endocrinol Metab 35: 330-333.
    OpenUrlCrossRefPubMed
  47. ↵
    Plateroti M, Gauthier K, Domon-Dell C, Freund JN, Samarut J, and Chassande O (2001) Functional interference between thyroid hormone receptor alpha (TRalpha) and natural truncated TRdeltaalpha isoforms in the control of intestine development. Mol Cell Biol 21: 4761-4772.
    OpenUrlAbstract/FREE Full Text
  48. ↵
    Quignodon L, Legrand C, Allioli N, Guadano-Ferraz A, Bernal J, Samarut J, and Flamant F (2004) Thyroid hormone signaling is highly heterogeneous during pre- and postnatal brain development. J Mol Endocrinol 33: 467-476.
    OpenUrlAbstract/FREE Full Text
  49. ↵
    Rastinejad F, Perlmann T, Evans RM, and Sigler PB (1995) Structural determinants of nuclear receptor assembly on DNA direct repeats. Nature (Lond) 375: 203-211.
    OpenUrlCrossRefPubMed
  50. ↵
    Ribeiro RC, Apriletti JW, Wagner RL, Feng W, Kushner PJ, Nilsson S, Scanlan TS, West BL, Fletterick RJ, and Baxter JD (1998) X-ray crystallographic and functional studies of thyroid hormone receptor. J Steroid Biochem Mol Biol 65: 133-141.
    OpenUrlCrossRefPubMed
  51. ↵
    Sap J, Munoz A, Damm K, Goldberg Y, Ghysdael J, Leutz A, Beug H, and Vennstrom B (1986) The c-erb-A protein is a high-affinity receptor for thyroid hormone. Nature (Lond) 324: 635-640.
    OpenUrlCrossRefPubMed
  52. ↵
    Schapira M, Raaka BM, Das S, Fan L, Totrov M, Zhou Z, Wilson SR, Abagyan R, and Samuels HH (2003) Discovery of diverse thyroid hormone receptor antagonists by high-throughput docking. Proc Natl Acad Sci USA 100: 7354-7359.
    OpenUrlAbstract/FREE Full Text
  53. ↵
    Thompson CC (1996) Thyroid hormone-responsive genes in developing cerebellum include a novel synaptotagmin and a hairless homolog. J Neurosci 16: 7832-7840.
    OpenUrlAbstract/FREE Full Text
  54. ↵
    Thompson CC, Weinberger C, Lebo R, and Evans RM (1987) Identification of a novel thyroid hormone receptor expressed in the mammalian central nervous system. Science (Wash DC) 237: 1610-1614.
    OpenUrlAbstract/FREE Full Text
  55. ↵
    Tinnikov A, Nordström K, Thoren P, Kindblom JM, Malin S, Rozell B, Adams M, Rajanayagam O, Petterson S, Ohlsson C, et al. (2002) Retardation of post-natal development caused by a negatively acting thyroid receptor alpha1. EMBO (Eur Mol Biol Organ) J 21: 1-9.
    OpenUrlAbstract
  56. ↵
    van Beeren HC, Bakker O, and Wiersinga WM (1995) Desethylamiodarone is a competitive inhibitor of the binding of thyroid hormone to the thyroid hormone alpha 1-receptor protein. Mol Cell Endocrinol 112: 15-19.
    OpenUrlCrossRefPubMed
  57. ↵
    van Beeren HC, Bakker O, and Wiersinga WM (1996) Structure-function relationship of the inhibition of the 3,5,3′-triiodothyronine binding to the alpha1- and beta1-thyroid hormone receptor by amiodarone analogs. Endocrinology 137: 2807-2814.
    OpenUrlCrossRefPubMed
  58. ↵
    van Beeren HC, Bakker O, and Wiersinga WM (2000) Desethylamiodarone interferes with the binding of co-activator GRIP-1 to the beta 1-thyroid hormone receptor. FEBS Lett 481: 213-216.
    OpenUrlCrossRefPubMed
  59. ↵
    van Beeren HC, Jong WM, Kaptein E, Visser TJ, Bakker O, Wiersinga WM, Zandieh Doulabi B, Platvoet-ter Schiphorst M, Labruyere WT, Lamers WH, et al. (2003) Dronerarone acts as a selective inhibitor of 3,5,3′-triiodothyronine binding to thyroid hormone receptor-alpha(1): in vitro and in vivo evidence. Endocrinology 144: 552-558.
    OpenUrlCrossRefPubMed
  60. ↵
    Vanacker JM, Bonnelye E, Delmarre C, and Laudet V (1998) Activation of the thyroid hormone receptor alpha gene promoter by the orphan nuclear receptor ERR alpha. Oncogene 17: 2429-2435.
    OpenUrlCrossRefPubMed
  61. ↵
    Viluksela M, Raasmaja A, Lebofsky M, Stahl BU, and Rozman KK (2004) Tissue-specific effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the activity of 5′-deiodinases I and II in rats. Toxicol Lett 147: 133-142.
    OpenUrlCrossRefPubMed
  62. ↵
    Wagner RL, Huber BR, Shiau AK, Kelly A, Cunha Lima ST, Scanlan TS, Apriletti JW, Baxter JD, West BL, and Fletterick RJ (2001) Hormone selectivity in thyroid hormone receptors. Mol Endocrinol 15: 398-410.
    OpenUrlCrossRefPubMed
  63. ↵
    Weinberger C, Thompson CC, Ong ES, Lebo R, Gruol DJ, and Evans RM (1986) The c-erb-A gene encodes a thyroid hormone receptor. Nature (Lond) 324: 641-646.
    OpenUrlCrossRefPubMed
  64. ↵
    Weiss RE and Refetoff S (2000) Resistance to thyroid hormone. Rev Endocr Metab Disord 1: 97-108.
    OpenUrlPubMed
  65. ↵
    Wikstrom L, Johansson C, Salto C, Barlow C, Campos Barros A, Baas F, Forrest D, Thoren P, and Vennstrom B (1998) Abnormal heart rate and body temperature in mice lacking thyroid hormone receptor alpha 1. EMBO (Eur Mol Biol Organ) J 17: 455-461.
    OpenUrlAbstract/FREE Full Text
  66. ↵
    Williams GR (2000) Cloning and characterization of two novel thyroid hormone receptor beta isoforms. Mol Cell Biol 20: 8329-8342.
    OpenUrlAbstract/FREE Full Text
  67. ↵
    Wondisford FE (2003) Thyroid hormone action: insight from transgenic mouse models. J Investig Med 51: 215-220.
    OpenUrlCrossRefPubMed
  68. ↵
    Yamada-Okabe T, Aono T, Sakai H, Kashima Y, and Yamada-Okabe H (2004) 2,3,7,8-tetrachlorodibenzo-p-dioxin augments the modulation of gene expression mediated by the thyroid hormone receptor. Toxicol Appl Pharmacol 194: 201-210.
    OpenUrlCrossRefPubMed
  69. ↵
    Yen PM (2001) Physiological and molecular basis of thyroid hormone action. Physiol Rev 81: 1097-1142.
    OpenUrlAbstract/FREE Full Text
  70. ↵
    Yen PM (2003) Molecular basis of resistance to thyroid hormone. Trends Endocrinol Metab 14: 327-333.
    OpenUrlCrossRefPubMed
  71. ↵
    Yen PM, Feng X, Flamant F, Chen Y, Walker RL, Weiss RE, Chassande O, Samarut J, Refetoff S, and Meltzer PS (2003) Effects of ligand and thyroid hormone receptor isoforms on hepatic gene expression profiles of thyroid hormone receptor knockout mice. EMBO Rep 4: 581-587.
    OpenUrlCrossRefPubMed
  72. ↵
    Zandieh-Doulabi B, Dop E, Schneiders M, Schiphorst MP, Mansen A, Vennstrom B, Dijkstra CD, Bakker O, and Wiersinga WM (2003) Zonal expression of the thyroid hormone receptor alpha isoforms in rodent liver. J Endocrinol 179: 379-385.
    OpenUrlAbstract
  73. ↵
    Zoeller RT, Bansal R, and Parris C (2005) Bisphenol-A, an environmental contaminant that acts as a thyroid hormone receptor antagonist in vitro, increases serum thyroxine, and alters RC3/neurogranin expression in the developing rat brain. Endocrinology 146: 607-612.
    OpenUrlCrossRefPubMed
  74. ↵
    Zoeller RT, Dowling AL, and Vas AA (2000) Developmental exposure to polychlorinated biphenyls exerts thyroid hormone-like effects on the expression of RC3/neurogranin and myelin basic protein messenger ribonucleic acids in the developing rat brain. Endocrinology 141: 181-189.
    OpenUrlCrossRefPubMed
  75. ↵
    Zoeller TR, Dowling AL, Herzig CT, Iannacone EA, Gauger KJ, and Bansal R (2002) Thyroid hormone brain development and the environment. Environ Health Perspect 110 (Suppl 3): 355-361.
    OpenUrlPubMed
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Pharmacological Reviews: 58 (4)
Pharmacological Reviews
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1 Dec 2006
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Research ArticleSpecial Issue IUPHAR Compendium of the Pharmacology and Classification of the Nuclear Receptor Superfamily 2006

International Union of Pharmacology. LIX. The Pharmacology and Classification of the Nuclear Receptor Superfamily: Thyroid Hormone Receptors

Frédéric Flamant, John D. Baxter, Douglas Forrest, Samuel Refetoff, Herbert Samuels, Tom S. Scanlan, Bjorn Vennström and Jacques Samarut
Pharmacological Reviews December 1, 2006, 58 (4) 705-711; DOI: https://doi.org/10.1124/pr.58.4.3

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Research ArticleSpecial Issue IUPHAR Compendium of the Pharmacology and Classification of the Nuclear Receptor Superfamily 2006

International Union of Pharmacology. LIX. The Pharmacology and Classification of the Nuclear Receptor Superfamily: Thyroid Hormone Receptors

Frédéric Flamant, John D. Baxter, Douglas Forrest, Samuel Refetoff, Herbert Samuels, Tom S. Scanlan, Bjorn Vennström and Jacques Samarut
Pharmacological Reviews December 1, 2006, 58 (4) 705-711; DOI: https://doi.org/10.1124/pr.58.4.3
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