TABLE 1

TRα

Receptor nomenclature NR1A1
Receptor code 4.10.1:TH:A1
Other names THRA, c-erbAα
Molecular information Hs: 410aa, P10827, chr. 17q11.21
Rn: 410aa, P63059, chr. 10q312
Mm: 410aa, Q542U8, chr. 11 D-E3
DNA binding
   Structure Monomer, heterodimer, RXR partner
   HRE core sequence AGGTCA (DR-4, palindrome)
Agonists TRIAC (154), T4 (14), reverse T3 (0.11)4; T3* (58 pM), GC-1 (440 pM) [Kd]5,6
Antagonists NH3 (20 nM) [Kd]5
Coactivators NCOA1, NCOA2, NCOA3, PPARBP7–10
Corepressors NCOR1, NCOR211,12
Biologically important isoforms TRα1{Hs, Mm, Rn}: main isoform: TRα2{Hs, Mm, Rn}: splice variant, DNA binding but no T3 binding, acts as antagonist13,14; TRδα1{Hs, Mm, Rn}: truncated, no DNA or T3 binding, acts as antagonist15; TRδα2{Hs, Mm, Rn}: truncated, no DNA or T3 binding, acts as antagonist15; TRα3{Mm}: splice variant, DNA binding but no T3 binding16
Tissue distribution Ubiquitous {Hs, Mm, Rn} [in situ hybridization]17
Functional assays Heart response {Mm}18
Main target genes Activated: Hr {Mm}, Hcn2 {Mm}19,20
Mutant phenotype Pleiotropic; usually viable and fertile {Mm} [knockout]18,21,22; knockin mutation-changing AF2 domain results in dwarfism and obesity {Mm} [knockin]23,24

  • aa, amino acids; chr., chromosome; PPARBP, peroxisome proliferator-activated receptor binding protein

  • ↵* Radioligand

  • ↵1. Masuda M, Yasuhara S, Yamashita M, Shibuya M, and Odaka T (1990) Nucleotide sequence of the murine thyroid hormone receptor (alpha-1) cDNA. Nucleic Acids Res 18: 3055

  • ↵2. Murray MB, Zilz ND, McCreary NL, MacDonald MJ, and Towle HC (1988) Isolation and characterization of rat cDNA clones for two distinct thyroid hormone receptors. J Biol Chem 263: 12770-12777

  • ↵3. Wood WM, Ocran KW, Gordon DF, and Ridgway EC (1991) Isolation and characterization of mouse complementary DNAs encoding alpha and beta thyroid hormone receptors from thyrotrope cells: the mouse pituitary-specific beta 2 isoform differs at the amino terminus from the corresponding species from rat pituitary tumor cells. Mol Endocrinol 5: 1049-1061

  • ↵4. Schueler PA, Schwartz HL, Strait KA, Mariash CN, and Oppenheimer JH (1990) Binding of 3,5,3′-triiodothyronine (T3) and its analogs to the in vitro translational products of c-erbA protooncogenes: differences in the affinity of the alpha- and beta-forms for the acetic acid analog and failure of the human testis and kidney alpha-2 products to bind T3. Mol Endocrinol 4: 227-234

  • ↵5. 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

  • ↵6. Sharma D and Fondell JD (2002) Ordered recruitment of histone acetyltransferases and the TRAP/Mediator complex to thyroid hormone-responsive promoters in vivo. Proc Natl Acad Sci USA 99: 7934-7939

  • ↵7. Chen H, Lin RJ, Schiltz RL, Chakravarti D, Nash A, Nagy L, Privalsky ML, Nakatani Y, and Evans RM (1997) Nuclear receptor coactivator ACTR is a novel histone acetyltransferase and forms a multimeric activation complex with P/CAF and CBP/p300. Cell 90: 569-580

  • ↵8. Ito M, Yuan CX, Okano HJ, Darnell RB, and Roeder RG (2000) Involvement of the TRAP220 component of the TRAP/SMCC coactivator complex in embryonic development and thyroid hormone action. Mol Cell 5: 683-693

  • ↵9. Ma H, Hong H, Huang SM, Irvine RA, Webb P, Kushner PJ, Coetzee GA, and Stallcup MR (1999) Multiple signal input and output domains of the 160-kilodalton nuclear receptor coactivator proteins. Mol Cell Biol 19: 6164-6173

  • ↵10. Nevado J, Tenbaum SP, and Aranda A (2004) hSrb7, an essential human Mediator component, acts as a coactivator for the thyroid hormone receptor. Mol Cell Endocrinol 222: 41-51

  • ↵11. Chen JD and Evans RM (1995) A transcriptional co-repressor that interacts with nuclear hormone receptors. Nature (Lond) 377: 454-457

  • ↵12. Horlein AJ, Naar AM, Heinzel T, Torchia J, Gloss B, Kurokawa R, Ryan A, Kamei Y, Soderstrom M, Glass CK, et al. (1995) Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor. Nature (Lond) 377: 397-404

  • ↵13. Mitsuhashi T, Tennyson GE, and Nikodem VM (1998) Alternative splicing generates messages encoding rat c-erbA proteins that do not bind thyroid hormone. Proc Natl Acad Sci USA 85: 5804-5808

  • ↵14. Nakai A, Seino S, Sakurai A, Szilak I, Bell GI, and DeGroot LJ (1998) Characterization of a thyroid hormone receptor expressed in human kidney and other tissues. Proc Natl Acad Sci USA 85: 2781-2785

  • ↵15. Chassande O, Fraichard A, Gauthier K, Flamant F, Legrand C, Savatier P, Laudet V, and Samarut J (1997) Identification of transcripts initiated from an internal promoter in the c-erbA alpha locus that encode inhibitors of retinoic acid receptor- alpha and triiodothyronine receptor activities. Mol Endocrinol 11: 1278-1290

  • ↵16. Prost E, Koenig RJ, Moore DD, Larsen PR, and Whalen RG (1988) Multiple sequences encoding potential thyroid hormone receptors isolated from mouse skeletal muscle cDNA libraries. Nucleic Acids Res 16: 6248

  • ↵17. Gray PA, Fu H, Luo P, Zhao Q, Yu J, Ferrari A, Tenzen T, Yuk DI, Tsung EF, Cai Z, et al. (2004) Mouse brain organization revealed through direct genome-scale TF expression analysis. Science 306: 2255-2257

  • ↵18. 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

  • ↵19. Gloss B, Sayen MR, Trost SU, Bluhm WF, Meyer M, Swanson EA, Usala SJ, and Dillmann WH (1999) Altered cardiac phenotype in transgenic mice carrying the delta337 threonine thyroid hormone receptor beta mutant derived from the S family. Endocrinology 140: 897-902

  • ↵20. Thompson CC (1996) Thyroid hormone-responsive genes in developing cerebellum include a novel synaptotagmin and a hairless homolog. J Neurosci 16: 7832-7840

  • ↵21. Fraichard A, Chassande O, Plateroti M, Roux JP, Trouillas J, Dehay C, Legrand C, Gauthier K, Kedinger M, Malaval L, et al. (1997) The T3R alpha gene encoding a thyroid hormone receptor is essential for post-natal development and thyroid hormone production. EMBO (Eur Mol Biol Org) J 16: 4412-4420

  • ↵22. Gauthier K, Chassande O, Plateroti M, Roux JP, Legrand C, Pain B, Rousset B, Weiss R, Trouillas J, and Samarut J (1999) Different functions for the thyroid hormone receptors TRalpha and TRbeta in the control of thyroid hormone production and post-natal development. EMBO (Eur Mol Biol Org) J 18: 623-631

  • ↵23. 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

  • ↵24. 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 Org) J 21: 1-9