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Abstract

  1. Top of page
  2. Abstract
  3. 1A. Thyroid Hormone Receptors
  4. 1B. Retinoic acid receptors
  5. 1C. Peroxisome proliferator-activated receptors
  6. 1D. Rev-Erb receptors
  7. 1F. Retinoic acid-related orphans
  8. 1H. Liver X receptor-like receptors
  9. 1I. Vitamin D receptor-like receptors
  10. 2A. Hepatocyte nuclear factor-4 receptors
  11. 2B. Retinoid X receptors
  12. 2C. Testicular receptors
  13. 2E. Tailless-like receptors
  14. 2F. COUP-TF-like receptors
  15. 3B. Estrogen-related receptors
  16. 4A. Nerve growth factor IB-like receptors
  17. 5A. Fushi tarazu F1-like receptors
  18. 6A. Germ cell nuclear factor receptors
  19. 0B. DAX-like receptors
  20. Steroid hormone receptors
  21. References

The Concise Guide to PHARMACOLOGY 2013/14 provides concise overviews of the key properties of over 2000 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.12444/full.

Nuclear hormone receptors are one of the seven major pharmacological targets into which the Guide is divided, with the others being G protein-coupled receptors, ligand-gated ion channels, ion channels, catalytic receptors, transporters and enzymes. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. A new landscape format has easy to use tables comparing related targets.

It is a condensed version of material contemporary to late 2013, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in previous Guides to Receptors and Channels. It is produced in conjunction with NC-IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR-DB and the Guide to Receptors and Channels, providing a permanent, citable, point-in-time record that will survive database updates.

An Introduction to Nuclear Hormone Receptors

Nuclear hormone receptors are specialised transcription factors with commonalities of sequence and structure, which bind as homo- or heterodimers to specific consensus sequences of DNA (response elements) in the promoter region of particular target genes. They regulate (either promoting or repressing) transcription of these target genes in response to a variety of endogenous ligands. Endogenous agonists are hydrophobic entities which, when bound to the receptor promote conformational changes in the receptor to allow recruitment (or dissociation) of protein partners, generating a large multiprotein complex.

Two major subclasses of nuclear hormone receptors with identified endogenous agonists can be identified: steroid and non-steroid hormone receptors. Steroid hormone receptors function typically as dimeric entities and are thought to be resident outside the nucleus in the unliganded state in a complex with chaperone proteins, which are liberated upon agonist binding. Migration to the nucleus and interaction with other regulators of gene transcription, including RNA polymerase, acetyltransferases and deacetylases, allows gene transcription to be regulated. Non-steroid hormone receptors typically exhibit a greater distribution in the nucleus in the unliganded state and interact with other nuclear hormone receptors to form heterodimers, as well as with other regulators of gene transcription, leading to changes in gene transcription upon agonist binding.

Selectivity of gene regulation is brought about through interaction of nuclear hormone receptors with particular consensus sequences of DNA, which are arranged typically as repeats or inverted palindromes to allow accumulation of multiple transcription factors in the promoter regions of genes.

Acknowledgements

We wish to acknowledge the tremendous help provided by the Consultants to the Guides past and present (see list in the Overview, p. 1452). We are also extremely grateful for the financial contributions from the British Pharmacological Society, the International Union of Basic and Clinical Pharmacology, the Wellcome Trust (099156/Z/12/Z]), which support the website and the University of Edinburgh, who host the guidetopharmacology.org website.

Conflict of interest

The authors state that there is no conflict of interest to disclose.

Further reading

Germain P, Staels B, Dacquet C, Spedding M, Laudet V. (2006) Overview of nomenclature of nuclear receptors. Pharmacol Rev 58: 685704.

  1. Top of page
  2. Abstract
  3. 1A. Thyroid Hormone Receptors
  4. 1B. Retinoic acid receptors
  5. 1C. Peroxisome proliferator-activated receptors
  6. 1D. Rev-Erb receptors
  7. 1F. Retinoic acid-related orphans
  8. 1H. Liver X receptor-like receptors
  9. 1I. Vitamin D receptor-like receptors
  10. 2A. Hepatocyte nuclear factor-4 receptors
  11. 2B. Retinoid X receptors
  12. 2C. Testicular receptors
  13. 2E. Tailless-like receptors
  14. 2F. COUP-TF-like receptors
  15. 3B. Estrogen-related receptors
  16. 4A. Nerve growth factor IB-like receptors
  17. 5A. Fushi tarazu F1-like receptors
  18. 6A. Germ cell nuclear factor receptors
  19. 0B. DAX-like receptors
  20. Steroid hormone receptors
  21. References
Overview

Thyroid hormone receptors (TRs, nomenclature as agreed by NC-IUPHAR Committee on Nuclear Receptors, [3]) are nuclear hormone receptors of the NR1A family, with diverse roles regulating macronutrient metabolism, cognition and cardiovascular homeostasis. TRs are activated by thyroxine (T4) and thyroid hormone (T3). Once activated by a ligand, the receptor acts as a transcription factor either as a monomer, homodimer or heterodimer with members of the retinoid X receptor family. NH-3 has been described as an antagonist at TRs with modest selectivity for TRβ [4].

NomenclatureThyroid hormone receptor-α Thyroid hormone receptor-β
Systematic nomenclatureNR1A1NR1A2
HGNC, UniProtTHRA, P10827 THRB, P10828
Rank order of potencyT3 > T4 T3 > T4
Selective agonists (pKi)GC-1 (pKd 10.17) [2, 5]
Comments

An interaction with integrin αVβ3 has been suggested to underlie plasma membrane localization of TRs and non-genomic signalling [1]. One splice variant, TRα2, lacks a functional DNA-binding domain and appears to act as a transcription suppressor.

Although radioligand binding assays have been described for these receptors, the radioligands are not commercially available.

Further reading

Bianco AC. (2011) Minireview: cracking the metabolic code for thyroid hormone signaling. Endocrinology 152: 33063311. [PMID:21712363]

Brent GA. (2012) Mechanisms of thyroid hormone action. J Clin Invest 122: 30353043. [PMID:22945636]

Flamant F, Baxter JD, Forrest D, Refetoff S, Samuels H, Scanlan TS, Vennström B, Samarut J. (2006) International Union of Pharmacology. LIX. The pharmacology and classification of the nuclear receptor superfamily: thyroid hormone receptors. Pharmacol Rev 58: 705711. [PMID:17132849]

Pramfalk C, Pedrelli M, Parini P. (2011) Role of thyroid receptor β in lipid metabolism. Biochim Biophys Acta 1812: 929937. [PMID:21194564]

Sirakov M, Plateroti M. (2011) The thyroid hormones and their nuclear receptors in the gut: from developmental biology to cancer. Biochim Biophys Acta 1812: 938946. [PMID:21194566]

Tancevski I, Rudling M, Eller P. (2011) Thyromimetics: a journey from bench to bed-side. Pharmacol Ther 131: 3339. [PMID:21504761]

  1. Top of page
  2. Abstract
  3. 1A. Thyroid Hormone Receptors
  4. 1B. Retinoic acid receptors
  5. 1C. Peroxisome proliferator-activated receptors
  6. 1D. Rev-Erb receptors
  7. 1F. Retinoic acid-related orphans
  8. 1H. Liver X receptor-like receptors
  9. 1I. Vitamin D receptor-like receptors
  10. 2A. Hepatocyte nuclear factor-4 receptors
  11. 2B. Retinoid X receptors
  12. 2C. Testicular receptors
  13. 2E. Tailless-like receptors
  14. 2F. COUP-TF-like receptors
  15. 3B. Estrogen-related receptors
  16. 4A. Nerve growth factor IB-like receptors
  17. 5A. Fushi tarazu F1-like receptors
  18. 6A. Germ cell nuclear factor receptors
  19. 0B. DAX-like receptors
  20. Steroid hormone receptors
  21. References
Overview

Retinoic acid receptors (nomenclature as agreed by NC-IUPHAR Committee on Nuclear Receptors, [8]) are nuclear hormone receptors of the NR1B family activated by the vitamin A-derived agonists all-trans-retinoic acid (ATRA) and 9-cis-retinoic acid, and the RAR-selective synthetic agonists TTNPB and adapalene.

NomenclatureRetinoic acid receptor-α Retinoic acid receptor-β Retinoic acid receptor-γ
Systematic nomenclatureNR1B1NR1B2NR1B3
HGNC, UniProtRARA, P10276 RARB, P10826 RARG, P13631
Selective agonists (pKi)Ro 40-6055[7, 11, 18], BMS753 (8.7) [10]AC261066 (pEC50 7.9 – 8.1) [15], AC55649 (pEC50 6.5 – 7.3) [15]AHPN[16]
Selective antagonists (pKi)Ro 41-5253 (pIC50 6.3 – 7.2) [6, 12]MM 11253[13]
Comments

Ro 41-5253 has been suggested to be a PPARγ agonist [17]. LE135 is an antagonist with selectivity for RARα and RARβ compared with RARγ [14]. [9] is a family-selective antagonist.

Further reading

Bour G, Lalevée S, Rochette-Egly C. (2007) Protein kinases and the proteasome join in the combinatorial control of transcription by nuclear retinoic acid receptors. Trends Cell Biol 17: 302309. [PMID:17467991]

Duong V, Rochette-Egly C. (2011) The molecular physiology of nuclear retinoic acid receptors. From health to disease. Biochim Biophys Acta 1812: 10231031. [PMID:20970498]

Germain P, Chambon P, Eichele G, Evans RM, Lazar MA, Leid M, De Lera AR, Lotan R, Mangelsdorf DJ, Gronemeyer H. (2006) International Union of Pharmacology. LX. Retinoic acid receptors. Pharmacol Rev 58: 712725. [PMID:17132850]

Maden M. (2007) Retinoic acid in the development, regeneration and maintenance of the nervous system. Nat Rev Neurosci 8: 755765. [PMID:17882253]

Mark M, Ghyselinck NB, Chambon P. (2006) Function of retinoid nuclear receptors: lessons from genetic and pharmacological dissections of the retinoic acid signaling pathway during mouse embryogenesis. Annu Rev Pharmacol Toxicol 46: 451480. [PMID:16402912]

  1. Top of page
  2. Abstract
  3. 1A. Thyroid Hormone Receptors
  4. 1B. Retinoic acid receptors
  5. 1C. Peroxisome proliferator-activated receptors
  6. 1D. Rev-Erb receptors
  7. 1F. Retinoic acid-related orphans
  8. 1H. Liver X receptor-like receptors
  9. 1I. Vitamin D receptor-like receptors
  10. 2A. Hepatocyte nuclear factor-4 receptors
  11. 2B. Retinoid X receptors
  12. 2C. Testicular receptors
  13. 2E. Tailless-like receptors
  14. 2F. COUP-TF-like receptors
  15. 3B. Estrogen-related receptors
  16. 4A. Nerve growth factor IB-like receptors
  17. 5A. Fushi tarazu F1-like receptors
  18. 6A. Germ cell nuclear factor receptors
  19. 0B. DAX-like receptors
  20. Steroid hormone receptors
  21. References
Overview

Peroxisome proliferator-activated receptors (PPARs, nomenclature as agreed by NC-IUPHAR Committee on Nuclear Receptors, [33]) are nuclear hormone receptors of the NR1C family, with diverse roles regulating lipid homeostasis, cellular differentiation, proliferation and the immune response. PPARs have many potential endogenous agonists [21, 33], including 15-deoxy-Δ12,14-PGJ2, prostacyclin (PGI2), many fatty acids and their oxidation products, lysophosphatidic acid (LPA) [32], 13-HODE, 15S-HETE, Paz-PC, azelaoyl-PAF and leukotriene B4 (LTB4). bezafibrate acts as a non-selective agonist for the PPAR family [41]. These receptors also bind hypolipidaemic drugs (PPARα) and anti-diabetic thiazolidinediones (PPARγ), as well as many non-steroidal anti-inflammatory drugs, such as sulindac and indomethacin. Once activated by a ligand, the receptor forms a heterodimer with members of the retinoid X receptor family and can act as a transcription factor. Although radioligand binding assays have been described for all three receptors, the radioligands are not commercially available. Commonly, receptor occupancy studies are conducted using fluorescent ligands and truncated forms of the receptor limited to the ligand binding domain.

NomenclaturePeroxisome proliferator-activated receptor-α Peroxisome proliferator-activated receptor-β/δ Peroxisome proliferator-activated receptor-γ
Systematic nomenclatureNR1C1NR1C2NR1C3
HGNC, UniProtPPARA, Q07869 PPARD, Q03181 PPARG, P37231
Selective agonists (pKi)ciprofibrate, GW7647 (pEC50 8.2) [22, 23], CP-775146 (pEC50 7.3) [28], pirinixic acid (pEC50 5.3) [41]GW501516 (pEC50 9.0) [35], GW0742X (pIC50 9.0) [25, 39]rosiglitazone (pKd 7.4) [27, 31, 44], GW1929 (8.8) [22], CDDO (Partial agonist) (8.0) [40], troglitazone (5.8) [19], ciglitazone (pEC50 4.6) [27], troglitazone (pIC50 6.3) [27, 44], pioglitazone (pIC50 6.2) [27, 37, 44]
Selective antagonists (pKi)GW6471 (pIC50 6.6) [42]GSK0660 (pIC50 6.5) [38]T0070907 (9.0) [29], CDDO-Me (6.9) [40], GW9662 (Irreversible inhibition) (pIC50 8.1) [30]
Comments

As with the estrogen receptor antagonists, many agents show tissue-selective efficacy (e.g. [20, 34, 36]). Agonists with mixed activity at PPARα and PPARγ have also been described (e.g[24, 26, 43]).

Further reading

Huang JV, Greyson CR, Schwartz GG. (2012) PPAR-γ as a therapeutic target in cardiovascular disease: evidence and uncertainty. J Lipid Res 53: 17381754. [PMID:22685322]

Michalik L, Auwerx J, Berger JP, Chatterjee VK, Glass CK, Gonzalez FJ, Grimaldi PA, Kadowaki T, Lazar MA, O'Rahilly S, Palmer CN, Plutzky J, Reddy JK, Spiegelman BM, Staels B, Wahli W. (2006) International Union of Pharmacology. LXI. Peroxisome proliferator-activated receptors. Pharmacol Rev 58: 726741. [PMID:17132851]

Michalik L, Wahli W. (2008) PPARs Mediate Lipid Signaling in Inflammation and Cancer. PPAR Res 2008: 134059. [PMID:19125181]

Peters JM, Shah YM, Gonzalez FJ. (2012) The role of peroxisome proliferator-activated receptors in carcinogenesis and chemoprevention. Nat Rev Cancer 12: 181195. [PMID:22318237]

Pirat C, Farce A, Lebègue N, Renault N, Furman C, Millet R, Yous S, Speca S, Berthelot P, Desreumaux P et al. (2012) Targeting peroxisome proliferator-activated receptors (PPARs): development of modulators. J Med Chem 55: 40274061. [PMID:22260081]

Varga T, Czimmerer Z, Nagy L. (2011) PPARs are a unique set of fatty acid regulated transcription factors controlling both lipid metabolism and inflammation. Biochim Biophys Acta 1812: 10071022. [PMID:21382489]

Youssef J, Badr M. (2011) Peroxisome proliferator-activated receptors and cancer: challenges and opportunities. Br J Pharmacol 164: 6882. [PMID:21449912]

  1. Top of page
  2. Abstract
  3. 1A. Thyroid Hormone Receptors
  4. 1B. Retinoic acid receptors
  5. 1C. Peroxisome proliferator-activated receptors
  6. 1D. Rev-Erb receptors
  7. 1F. Retinoic acid-related orphans
  8. 1H. Liver X receptor-like receptors
  9. 1I. Vitamin D receptor-like receptors
  10. 2A. Hepatocyte nuclear factor-4 receptors
  11. 2B. Retinoid X receptors
  12. 2C. Testicular receptors
  13. 2E. Tailless-like receptors
  14. 2F. COUP-TF-like receptors
  15. 3B. Estrogen-related receptors
  16. 4A. Nerve growth factor IB-like receptors
  17. 5A. Fushi tarazu F1-like receptors
  18. 6A. Germ cell nuclear factor receptors
  19. 0B. DAX-like receptors
  20. Steroid hormone receptors
  21. References
Overview

Rev-erb receptors (nomenclature as agreed by NC-IUPHAR committee on nuclear hormone receptors [45]) have yet to be officially paired with an endogenous ligand, but are thought to be activated by heme.

NomenclatureRev-Erb-α Rev-Erb-β
Systematic nomenclatureNR1D1NR1D2
HGNC, UniProtNR1D1, P20393 NR1D2, Q14995
Endogenous agonists (pKi)heme (Selective) [48, 49]heme (Selective) [48, 49]
Selective agonists (pKi)GSK4112 (pEC50 6.4) [46], GSK4112 (pIC50 5.6) [47]
Selective antagonists (pKi)SR8278 (pIC50 6.5) [47]

Further reading

Benoit G, Cooney A, Giguere V, Ingraham H, Lazar M, Muscat G, Perlmann T, Renaud JP, Schwabe J, Sladek F, Tsai MJ, Laudet V. (2006) International Union of Pharmacology. LXVI. Orphan nuclear receptors. Pharmacol Rev 58: 798836. [PMID:17132856]

Duez H, Staels B. (2009) Rev-erb-alpha: an integrator of circadian rhythms and metabolism. J Appl Physiol 107: 19721980. [PMID:19696364]

Germain P, Staels B, Dacquet C, Spedding M, Laudet V. (2006) Overview of nomenclature of nuclear receptors. Pharmacol Rev 58: 685704. [PMID:17132848]

Huang P, Chandra V, Rastinejad F. (2010) Structural overview of the nuclear receptor superfamily: insights into physiology and therapeutics. Annu Rev Physiol 72: 247272. [PMID:20148675]

Phelan CA, Gampe RT, Lambert MH, Parks DJ, Montana V, Bynum J, Broderick TM, Hu X, Williams SP, Nolte RT, Lazar MA. (2010) Structure of Rev-erbalpha bound to N-CoR reveals a unique mechanism of nuclear receptor-co-repressor interaction. Nat Struct Mol Biol 17: 808814. [PMID:20581824]

Sladek FM. (2011) What are nuclear receptor ligands?. Mol Cell Endocrinol 334: 313. [PMID:20615454]

Yin L, Wu N, Lazar MA. (2010) Nuclear receptor Rev-erbalpha: a heme receptor that coordinates circadian rhythm and metabolism. Nucl Recept Signal 8: e001. [PMID:20414452]

  1. Top of page
  2. Abstract
  3. 1A. Thyroid Hormone Receptors
  4. 1B. Retinoic acid receptors
  5. 1C. Peroxisome proliferator-activated receptors
  6. 1D. Rev-Erb receptors
  7. 1F. Retinoic acid-related orphans
  8. 1H. Liver X receptor-like receptors
  9. 1I. Vitamin D receptor-like receptors
  10. 2A. Hepatocyte nuclear factor-4 receptors
  11. 2B. Retinoid X receptors
  12. 2C. Testicular receptors
  13. 2E. Tailless-like receptors
  14. 2F. COUP-TF-like receptors
  15. 3B. Estrogen-related receptors
  16. 4A. Nerve growth factor IB-like receptors
  17. 5A. Fushi tarazu F1-like receptors
  18. 6A. Germ cell nuclear factor receptors
  19. 0B. DAX-like receptors
  20. Steroid hormone receptors
  21. References
Overview

Retinoic acid receptor-related orphan receptors (ROR, nomenclature as agreed by NC-IUPHAR Committee on Nuclear Receptors, [50]) have yet to be assigned a definitive endogenous ligand, although RORα may be synthesized with a ‘captured’ agonist such as cholesterol[52, 53].

NomenclatureRAR-related orphan receptor-α RAR-related orphan receptor-β RAR-related orphan receptor-γ
Systematic nomenclatureNR1F1NR1F2NR1F3
HGNC, UniProtRORA, P35398 RORB, Q92753 RORC, P51449
Endogenous agonists (pKi)cholesterol (Selective) [53, 54]
Selective agonists (pKi)7-hydroxycholesterol[51], cholesterol sulphate[51, 53]
Comments

all-trans-retinoic acid shows selectivity for RORβ within the ROR family [55]. RORα has been suggested to be a nuclear receptor responding to melatonin[56].

Further reading

Benoit G, Cooney A, Giguere V, Ingraham H, Lazar M, Muscat G, Perlmann T, Renaud JP, Schwabe J, Sladek F, Tsai MJ, Laudet V. (2006) International Union of Pharmacology. LXVI. Orphan nuclear receptors. Pharmacol Rev 58: 798836. [PMID:17132856]

  1. Top of page
  2. Abstract
  3. 1A. Thyroid Hormone Receptors
  4. 1B. Retinoic acid receptors
  5. 1C. Peroxisome proliferator-activated receptors
  6. 1D. Rev-Erb receptors
  7. 1F. Retinoic acid-related orphans
  8. 1H. Liver X receptor-like receptors
  9. 1I. Vitamin D receptor-like receptors
  10. 2A. Hepatocyte nuclear factor-4 receptors
  11. 2B. Retinoid X receptors
  12. 2C. Testicular receptors
  13. 2E. Tailless-like receptors
  14. 2F. COUP-TF-like receptors
  15. 3B. Estrogen-related receptors
  16. 4A. Nerve growth factor IB-like receptors
  17. 5A. Fushi tarazu F1-like receptors
  18. 6A. Germ cell nuclear factor receptors
  19. 0B. DAX-like receptors
  20. Steroid hormone receptors
  21. References
Overview

Liver X and farnesoid X receptors (LXR and FXR, nomenclature as agreed by NC-IUPHAR Committee on Nuclear Receptors, [62]) are members of a steroid analogue-activated nuclear receptor subfamily (ENSFM00500000269785), which form heterodimers with members of the retinoid X receptor family. Endogenous ligands for LXRs include hydroxycholesterols (OHC), while FXRs appear to be activated by bile acids.

NomenclatureFarnesoid X receptor Farnesoid X receptor-β Liver X receptor-α Liver X receptor-β
Systematic nomenclatureNR1H4NR1H5NR1H3NR1H2
HGNC, UniProtNR1H4, Q96RI1 NR1H5P, -NR1H3, Q13133 NR1H2, P55055
Potency orderchenodeoxycholic acid > lithocholic acid, deoxycholic acid[60, 64]20S-hydroxycholesterol, 22R-hydroxycholesterol, 24(S)-hydroxycholesterol > 25-hydroxycholesterol, 27-hydroxycholesterol[59]20S-hydroxycholesterol, 22R-hydroxycholesterol, 24(S)-hydroxycholesterol > 25-hydroxycholesterol, 27-hydroxycholesterol[59]
Selective agonists (pKi)GW4064 (pEC50 7.8) [61], ECDCA (pEC50 7.0) [65], fexaramine (pEC50 6.6) [58]
Selective antagonists (pKi)guggulsterone (pIC50 5.7 – 6.0) [67]
Endogenous agonists (pKi)lanosterol (pEC50 6.0 - Mouse) [63]
Comments

T0901317[66] and GW3965[57] are synthetic agonists acting at both LXRα and LXRβ with less than 10-fold selectivity. NR1H5P (FXRβ) is a pseudogene in man, but active in the mouse.

Further reading

A-González N, Castrillo A. (2011) Liver X receptors as regulators of macrophage inflammatory and metabolic pathways. Biochim Biophys Acta 1812: 982994. [PMID:21193033]

Calkin AC, Tontonoz P. (2010) Liver x receptor signaling pathways and atherosclerosis. Arterioscler Thromb Vasc Biol 30: 15131518. [PMID:20631351]

Chen WD, Wang YD, Meng Z, Zhang L, Huang W. (2011) Nuclear bile acid receptor FXR in the hepatic regeneration. Biochim Biophys Acta 1812: 888892. [PMID:21167938]

Claudel T, Zollner G, Wagner M, Trauner M. (2011) Role of nuclear receptors for bile acid metabolism, bile secretion, cholestasis, and gallstone disease. Biochim Biophys Acta 1812: 867878. [PMID:21194565]

El-Hajjaji FZ, Oumeddour A, Pommier AJ, Ouvrier A, Viennois E, Dufour J, Caira F, Drevet JR, Volle DH, Baron S et al. (2011) Liver X receptors, lipids and their reproductive secrets in the male. Biochim Biophys Acta 1812: 974981. [PMID:21334438]

Gadaleta RM, van Mil SW, Oldenburg B, Siersema PD, Klomp LW, van Erpecum KJ. (2010) Bile acids and their nuclear receptor FXR: Relevance for hepatobiliary and gastrointestinal disease. Biochim Biophys Acta 1801: 683692. [PMID:20399894]

Gardmo C, Tamburro A, Modica S, Moschetta A. (2011) Proteomics for the discovery of nuclear bile acid receptor FXR targets. Biochim Biophys Acta 1812: 836841. [PMID:21439373]

Hageman J, Herrema H, Groen AK, Kuipers F. (2010) A role of the bile salt receptor FXR in atherosclerosis. Arterioscler Thromb Vasc Biol 30: 15191528. [PMID:20631352]

Kemper JK. (2011) Regulation of FXR transcriptional activity in health and disease: Emerging roles of FXR cofactors and post-translational modifications. Biochim Biophys Acta 1812: 842850. [PMID:21130162]

Matsubara T, Li F, Gonzalez FJ. (2013) FXR signaling in the enterohepatic system. Mol Cell Endocrinol 368: 1729. [PMID:22609541]

Mencarelli A, Fiorucci S. (2010) FXR an emerging therapeutic target for the treatment of atherosclerosis. J Cell Mol Med 14: 7992. [PMID:20041971]

Moore DD, Kato S, Xie W, Mangelsdorf DJ, Schmidt DR, Xiao R, Kliewer SA. (2006) International Union of Pharmacology. LXII. The NR1H and NR1I receptors: constitutive androstane receptor, pregnene X receptor, farnesoid X receptor alpha, farnesoid X receptor beta, liver X receptor alpha, liver X receptor beta, and vitamin D receptor. Pharmacol Rev 58: 742759. [PMID:17132852]

  1. Top of page
  2. Abstract
  3. 1A. Thyroid Hormone Receptors
  4. 1B. Retinoic acid receptors
  5. 1C. Peroxisome proliferator-activated receptors
  6. 1D. Rev-Erb receptors
  7. 1F. Retinoic acid-related orphans
  8. 1H. Liver X receptor-like receptors
  9. 1I. Vitamin D receptor-like receptors
  10. 2A. Hepatocyte nuclear factor-4 receptors
  11. 2B. Retinoid X receptors
  12. 2C. Testicular receptors
  13. 2E. Tailless-like receptors
  14. 2F. COUP-TF-like receptors
  15. 3B. Estrogen-related receptors
  16. 4A. Nerve growth factor IB-like receptors
  17. 5A. Fushi tarazu F1-like receptors
  18. 6A. Germ cell nuclear factor receptors
  19. 0B. DAX-like receptors
  20. Steroid hormone receptors
  21. References
Overview

Vitamin D (VDR), Pregnane X (PXR) and Constitutive Androstane (CAR) receptors (nomenclature as agreed by NC-IUPHAR Committee on Nuclear Receptors, [79]) are members of the NR1I family of nuclear receptors, which form heterodimers with members of the retinoid X receptor family. PXR and CAR are activated by a range of exogenous compounds, with no established endogenous physiological agonists, although high concentrations of bile acids and bile pigments activate PXR and CAR[79].

NomenclatureVitamin D receptor Pregnane X receptor Constitutive androstane receptor
Systematic nomenclatureNR1I1NR1I2NR1I3
HGNC, UniProtVDR, P11473 NR1I2, O75469 NR1I3, Q14994
Endogenous agonists (pKi)1,25-dihydroxyvitamin D3 (pKd 8.9 – 9.2) [68, 71]17β-estradiol (Selective) [74]
Selective agonists (pKi)EB1089 (pKd 9.57) [70, 84]hyperforin (pEC50 7.6) [80, 83], rifampicin (pEC50 5.5 – 6.0) [69, 76], lovastatin (pEC50 5.3 – 6.0) [76], pregnanedione (pIC50 6.4) [74]TCPOBOP (pEC50 7.7 - Mouse) [82], CITCO (pEC50 7.3) [77]
Selective antagonists (pKi)TEI-9647[78], ZK159222 (pIC50 7.5) [72, 73]
Commentclotrimazole[81] and T0901317[75] although acting at other sites, function as antagonists of the constitutive androstane receptor

Further reading

Bikle DD. (2011) Vitamin D: an ancient hormone. Exp Dermatol 20: 713. [PMID:21197695]

Campbell FC, Xu H, El-Tanani M, Crowe P, Bingham V. (2010) The yin and yang of vitamin D receptor (VDR) signaling in neoplastic progression: operational networks and tissue-specific growth control. Biochem Pharmacol 79: 19. [PMID:19737544]

Chen Y, Tang Y, Guo C, Wang J, Boral D, Nie D. (2012) Nuclear receptors in the multidrug resistance through the regulation of drug-metabolizing enzymes and drug transporters. Biochem Pharmacol 83: 11121126. [PMID:22326308]

Cheng J, Shah YM, Gonzalez FJ. (2012) Pregnane X receptor as a target for treatment of inflammatory bowel disorders. Trends Pharmacol Sci 33: 323330. [PMID:22609277]

Ihunnah CA, Jiang M, Xie W. (2011) Nuclear receptor PXR, transcriptional circuits and metabolic relevance. Biochim Biophys Acta 1812: 956963. [PMID:21295138]

Kachaylo EM, Pustylnyak VO, Lyakhovich VV, Gulyaeva LF. (2011) Constitutive androstane receptor (CAR) is a xenosensor and target for therapy. Biochemistry Mosc 76: 10871097. [PMID:22098234]

Krishnan AV, Feldman D. (2011) Mechanisms of the anti-cancer and anti-inflammatory actions of vitamin D. Annu Rev Pharmacol Toxicol 51: 311336. [PMID:20936945]

Moore DD, Kato S, Xie W, Mangelsdorf DJ, Schmidt DR, Xiao R, Kliewer SA. (2006) International Union of Pharmacology. LXII. The NR1H and NR1I receptors: constitutive androstane receptor, pregnene X receptor, farnesoid X receptor alpha, farnesoid X receptor beta, liver X receptor alpha, liver X receptor beta, and vitamin D receptor. Pharmacol Rev 58: 742759. [PMID:17132852]

Plum LA, DeLuca HF. (2010) Vitamin D, disease and therapeutic opportunities. Nat Rev Drug Discov 9: 941955. [PMID:21119732]

Staudinger JL, Woody S, Sun M, Cui W. (2013) Nuclear-receptor-mediated regulation of drug- and bile-acid-transporter proteins in gut and liver. Drug Metab Rev 45: 4859. [PMID:23330541]

  1. Top of page
  2. Abstract
  3. 1A. Thyroid Hormone Receptors
  4. 1B. Retinoic acid receptors
  5. 1C. Peroxisome proliferator-activated receptors
  6. 1D. Rev-Erb receptors
  7. 1F. Retinoic acid-related orphans
  8. 1H. Liver X receptor-like receptors
  9. 1I. Vitamin D receptor-like receptors
  10. 2A. Hepatocyte nuclear factor-4 receptors
  11. 2B. Retinoid X receptors
  12. 2C. Testicular receptors
  13. 2E. Tailless-like receptors
  14. 2F. COUP-TF-like receptors
  15. 3B. Estrogen-related receptors
  16. 4A. Nerve growth factor IB-like receptors
  17. 5A. Fushi tarazu F1-like receptors
  18. 6A. Germ cell nuclear factor receptors
  19. 0B. DAX-like receptors
  20. Steroid hormone receptors
  21. References
Overview

Hepatocyte nuclear factor-4 receptors (nomenclature as agreed by NC-IUPHAR committee on nuclear hormone receptors [85]) have yet to be officially paired with an endogenous ligand, although linoleic acid has been described to activate HNF4α receptors.

NomenclatureHepatocyte nuclear factor-4-α Hepatocyte nuclear factor-4-γ
Systematic nomenclatureNR2A1NR2A2
HGNC, UniProtHNF4A, P41235 HNF4G, Q14541
Endogenous agonists (pKi)linoleic acid (Selective) [87]
Selective antagonists (pKi)BI6015[86]

Further reading

Benoit G, Cooney A, Giguere V, Ingraham H, Lazar M, Muscat G, Perlmann T, Renaud JP, Schwabe J, Sladek F, Tsai MJ, Laudet V. (2006) International Union of Pharmacology. LXVI. Orphan nuclear receptors. Pharmacol Rev 58: 798836. [PMID:17132856]

Germain P, Staels B, Dacquet C, Spedding M, Laudet V. (2006) Overview of nomenclature of nuclear receptors. Pharmacol Rev 58: 685704. [PMID:17132848]

Huang P, Chandra V, Rastinejad F. (2010) Structural overview of the nuclear receptor superfamily: insights into physiology and therapeutics. Annu Rev Physiol 72: 247272. [PMID:20148675]

Hwang-Verslues WW, Sladek FM. (2010) HNF4α–role in drug metabolism and potential drug target?. Curr Opin Pharmacol 10: 698705. [PMID:20833107]

Sladek FM. (2011) What are nuclear receptor ligands?. Mol Cell Endocrinol 334: 313. [PMID:20615454]

  1. Top of page
  2. Abstract
  3. 1A. Thyroid Hormone Receptors
  4. 1B. Retinoic acid receptors
  5. 1C. Peroxisome proliferator-activated receptors
  6. 1D. Rev-Erb receptors
  7. 1F. Retinoic acid-related orphans
  8. 1H. Liver X receptor-like receptors
  9. 1I. Vitamin D receptor-like receptors
  10. 2A. Hepatocyte nuclear factor-4 receptors
  11. 2B. Retinoid X receptors
  12. 2C. Testicular receptors
  13. 2E. Tailless-like receptors
  14. 2F. COUP-TF-like receptors
  15. 3B. Estrogen-related receptors
  16. 4A. Nerve growth factor IB-like receptors
  17. 5A. Fushi tarazu F1-like receptors
  18. 6A. Germ cell nuclear factor receptors
  19. 0B. DAX-like receptors
  20. Steroid hormone receptors
  21. References
Overview

Retinoid X receptors (nomenclature as agreed by NC-IUPHAR Committee on Nuclear Receptors, [90]) are NR2B family members activated by 9-cis-retinoic acid and the RXR-selective agonists bexarotene and LG100268, sometimes referred to as rexinoids. UVI3003[93] and HX531 [89] have been described as a pan-RXR antagonists. These receptors form RXR–RAR heterodimers and RXR–RXR homodimers [88, 92].

NomenclatureRetinoid X receptor-α Retinoid X receptor-β Retinoid X receptor-γ
Systematic nomenclatureNR2B1NR2B2NR2B3
HGNC, UniProtRXRA, P19793 RXRB, P28702 RXRG, P48443
Selective agonists (pKi)CD3254 (pIC50 8.5) [91]

Further reading

Bour G, Lalevée S, Rochette-Egly C. (2007) Protein kinases and the proteasome join in the combinatorial control of transcription by nuclear retinoic acid receptors. Trends Cell Biol 17: 302309. [PMID:17467991]

Duong V, Rochette-Egly C. (2011) The molecular physiology of nuclear retinoic acid receptors. From health to disease. Biochim Biophys Acta 1812: 10231031. [PMID:20970498]

Germain P, Chambon P, Eichele G, Evans RM, Lazar MA, Leid M, De Lera AR, Lotan R, Mangelsdorf DJ, Gronemeyer H. (2006) International Union of Pharmacology. LXIII. Retinoid X receptors. Pharmacol Rev 58: 760772. [PMID:17132853]

Lefebvre P, Benomar Y, Staels B. (2010) Retinoid X receptors: common heterodimerization partners with distinct functions. Trends Endocrinol Metab 21: 676683. [PMID:20674387]

Maden M. (2007) Retinoic acid in the development, regeneration and maintenance of the nervous system. Nat Rev Neurosci 8: 755765. [PMID:17882253]

Mark M, Ghyselinck NB, Chambon P. (2006) Function of retinoid nuclear receptors: lessons from genetic and pharmacological dissections of the retinoic acid signaling pathway during mouse embryogenesis. Annu Rev Pharmacol Toxicol 46: 451480. [PMID:16402912]

Pérez E, Bourguet W, Gronemeyer H, de Lera AR. (2011) Modulation of RXR function through ligand design. Biochim Biophys Acta [Epub ahead of print]. [PMID:21515403]

  1. Top of page
  2. Abstract
  3. 1A. Thyroid Hormone Receptors
  4. 1B. Retinoic acid receptors
  5. 1C. Peroxisome proliferator-activated receptors
  6. 1D. Rev-Erb receptors
  7. 1F. Retinoic acid-related orphans
  8. 1H. Liver X receptor-like receptors
  9. 1I. Vitamin D receptor-like receptors
  10. 2A. Hepatocyte nuclear factor-4 receptors
  11. 2B. Retinoid X receptors
  12. 2C. Testicular receptors
  13. 2E. Tailless-like receptors
  14. 2F. COUP-TF-like receptors
  15. 3B. Estrogen-related receptors
  16. 4A. Nerve growth factor IB-like receptors
  17. 5A. Fushi tarazu F1-like receptors
  18. 6A. Germ cell nuclear factor receptors
  19. 0B. DAX-like receptors
  20. Steroid hormone receptors
  21. References
Overview

Testicular receptors (nomenclature as agreed by NC-IUPHAR committee on nuclear hormone receptors [94]) have yet to be officially paired with an endogenous ligand, although testicular receptor 4 has been reported to respond to retinoids.

NomenclatureTesticular receptor 2 Testicular receptor 4
Systematic nomenclatureNR2C1NR2C2
HGNC, UniProtNR2C1, P13056 NR2C2, P49116
Endogenous agonists (pKi)all-trans-retinoic acid (Selective) [96], retinol (Selective) [96]
CommentForms a heterodimer with TR4; gene disruption appears without effect on testicular development or function [95]Forms a heterodimer with TR2

Further reading

Benoit G, Cooney A, Giguere V, Ingraham H, Lazar M, Muscat G, Perlmann T, Renaud JP, Schwabe J, Sladek F, Tsai MJ, Laudet V. (2006) International Union of Pharmacology. LXVI. Orphan nuclear receptors. Pharmacol Rev 58: 798836. [PMID:17132856]

Duez H, Staels B. (2009) Rev-erb-alpha: an integrator of circadian rhythms and metabolism. J Appl Physiol 107: 19721980. [PMID:19696364]

Germain P, Staels B, Dacquet C, Spedding M, Laudet V. (2006) Overview of nomenclature of nuclear receptors. Pharmacol Rev 58: 685704. [PMID:17132848]

Huang P, Chandra V, Rastinejad F. (2010) Structural overview of the nuclear receptor superfamily: insights into physiology and therapeutics. Annu Rev Physiol 72: 247272. [PMID:20148675]

Phelan CA, Gampe RT, Lambert MH, Parks DJ, Montana V, Bynum J, Broderick TM, Hu X, Williams SP, Nolte RT, Lazar MA. (2010) Structure of Rev-erbalpha bound to N-CoR reveals a unique mechanism of nuclear receptor-co-repressor interaction. Nat Struct Mol Biol 17: 808814. [PMID:20581824]

Schimmer BP, White PC. (2010) Minireview: steroidogenic factor 1: its roles in differentiation, development, and disease. Mol Endocrinol 24: 13221337. [PMID:20203099]

Sladek FM. (2011) What are nuclear receptor ligands?. Mol Cell Endocrinol 334: 313. [PMID:20615454]

Yin L, Wu N, Lazar MA. (2010) Nuclear receptor Rev-erbalpha: a heme receptor that coordinates circadian rhythm and metabolism. Nucl Recept Signal 8: e001. [PMID:20414452]

Zhang Y, Hagedorn CH, Wang L. (2011) Role of nuclear receptor SHP in metabolism and cancer. Biochim Biophys Acta 1812: 893908. [PMID:20970497]

Zhao Y, Bruemmer D. (2010) NR4A orphan nuclear receptors: transcriptional regulators of gene expression in metabolism and vascular biology. Arterioscler Thromb Vasc Biol 30: 15351541. [PMID:20631354]

  1. Top of page
  2. Abstract
  3. 1A. Thyroid Hormone Receptors
  4. 1B. Retinoic acid receptors
  5. 1C. Peroxisome proliferator-activated receptors
  6. 1D. Rev-Erb receptors
  7. 1F. Retinoic acid-related orphans
  8. 1H. Liver X receptor-like receptors
  9. 1I. Vitamin D receptor-like receptors
  10. 2A. Hepatocyte nuclear factor-4 receptors
  11. 2B. Retinoid X receptors
  12. 2C. Testicular receptors
  13. 2E. Tailless-like receptors
  14. 2F. COUP-TF-like receptors
  15. 3B. Estrogen-related receptors
  16. 4A. Nerve growth factor IB-like receptors
  17. 5A. Fushi tarazu F1-like receptors
  18. 6A. Germ cell nuclear factor receptors
  19. 0B. DAX-like receptors
  20. Steroid hormone receptors
  21. References
Overview

Tailless-like receptors (nomenclature as agreed by NC-IUPHAR committee on nuclear hormone receptors [97]) have yet to be officially paired with an endogenous ligand.

NomenclatureTLX PNR
Systematic nomenclatureNR2E1NR2E3
HGNC, UniProtNR2E1, Q9Y466 NR2E3, Q9Y5X4
CommentGene disruption is associated with abnormal brain development [98, 99]

Further reading

Benoit G, Cooney A, Giguere V, Ingraham H, Lazar M, Muscat G, Perlmann T, Renaud JP, Schwabe J, Sladek F, Tsai MJ, Laudet V. (2006) International Union of Pharmacology. LXVI. Orphan nuclear receptors. Pharmacol Rev 58: 798836. [PMID:17132856]

Germain P, Staels B, Dacquet C, Spedding M, Laudet V. (2006) Overview of nomenclature of nuclear receptors. Pharmacol Rev 58: 685704. [PMID:17132848]

Gui H, Li ML, Tsai CC. (2011) A tale of tailless. Dev Neurosci 33: 113. [PMID:21124006]

Huang P, Chandra V, Rastinejad F. (2010) Structural overview of the nuclear receptor superfamily: insights into physiology and therapeutics. Annu Rev Physiol 72: 247272. [PMID:20148675]

Sladek FM. (2011) What are nuclear receptor ligands?. Mol Cell Endocrinol 334: 313. [PMID:20615454]

  1. Top of page
  2. Abstract
  3. 1A. Thyroid Hormone Receptors
  4. 1B. Retinoic acid receptors
  5. 1C. Peroxisome proliferator-activated receptors
  6. 1D. Rev-Erb receptors
  7. 1F. Retinoic acid-related orphans
  8. 1H. Liver X receptor-like receptors
  9. 1I. Vitamin D receptor-like receptors
  10. 2A. Hepatocyte nuclear factor-4 receptors
  11. 2B. Retinoid X receptors
  12. 2C. Testicular receptors
  13. 2E. Tailless-like receptors
  14. 2F. COUP-TF-like receptors
  15. 3B. Estrogen-related receptors
  16. 4A. Nerve growth factor IB-like receptors
  17. 5A. Fushi tarazu F1-like receptors
  18. 6A. Germ cell nuclear factor receptors
  19. 0B. DAX-like receptors
  20. Steroid hormone receptors
  21. References
Overview

COUP-TF-like receptors (nomenclature as agreed by NC-IUPHAR committee on nuclear hormone receptors [100]) have yet to be officially paired with an endogenous ligand.

NomenclatureCOUP-TF1 COUP-TF2 V-erbA-related gene
Systematic nomenclatureNR2F1NR2F2NR2F6
HGNC, UniProtNR2F1, P10589 NR2F2, P24468 NR2F6, P10588
CommentGene disruption is perinatally lethal [102]Gene disruption is embryonically lethal [101]Gene disruption impairs CNS development [103]

Further reading

Benoit G, Cooney A, Giguere V, Ingraham H, Lazar M, Muscat G, Perlmann T, Renaud JP, Schwabe J, Sladek F, Tsai MJ, Laudet V. (2006) International Union of Pharmacology. LXVI. Orphan nuclear receptors. Pharmacol Rev 58: 798836. [PMID:17132856]

Germain P, Staels B, Dacquet C, Spedding M, Laudet V. (2006) Overview of nomenclature of nuclear receptors. Pharmacol Rev 58: 685704. [PMID:17132848]

Huang P, Chandra V, Rastinejad F. (2010) Structural overview of the nuclear receptor superfamily: insights into physiology and therapeutics. Annu Rev Physiol 72: 247272. [PMID:20148675]

Lin FJ, Qin J, Tang K, Tsai SY, Tsai MJ. (2011) Coup d'Etat: an orphan takes control. Endocr Rev 32: 404421. [PMID:21257780]

Sladek FM. (2011) What are nuclear receptor ligands?. Mol Cell Endocrinol 334: 313. [PMID:20615454]

  1. Top of page
  2. Abstract
  3. 1A. Thyroid Hormone Receptors
  4. 1B. Retinoic acid receptors
  5. 1C. Peroxisome proliferator-activated receptors
  6. 1D. Rev-Erb receptors
  7. 1F. Retinoic acid-related orphans
  8. 1H. Liver X receptor-like receptors
  9. 1I. Vitamin D receptor-like receptors
  10. 2A. Hepatocyte nuclear factor-4 receptors
  11. 2B. Retinoid X receptors
  12. 2C. Testicular receptors
  13. 2E. Tailless-like receptors
  14. 2F. COUP-TF-like receptors
  15. 3B. Estrogen-related receptors
  16. 4A. Nerve growth factor IB-like receptors
  17. 5A. Fushi tarazu F1-like receptors
  18. 6A. Germ cell nuclear factor receptors
  19. 0B. DAX-like receptors
  20. Steroid hormone receptors
  21. References
Overview

Estrogen-related receptors (nomenclature as agreed by NC-IUPHAR committee on nuclear hormone receptors [104]) have yet to be officially paired with an endogenous ligand.

NomenclatureEstrogen-related receptor-α Estrogen-related receptor-β Estrogen-related receptor-γ
Systematic nomenclatureNR3B1NR3B2NR3B3
HGNC, UniProtESRRA, P11474 ESRRB, O95718 ESRRG, P62508
CommentActivated by some dietary flavonoids [105]; activated by the synthetic agonist GSK4716[108] and blocked by XCT790[106]May be activated by DY131[107]May be activated by DY131[107]

Further reading

Benoit G, Cooney A, Giguere V, Ingraham H, Lazar M, Muscat G, Perlmann T, Renaud JP, Schwabe J, Sladek F, Tsai MJ, Laudet V. (2006) International Union of Pharmacology. LXVI. Orphan nuclear receptors. Pharmacol Rev 58: 798836. [PMID:17132856]

Deblois G, Giguère V. (2011) Functional and physiological genomics of estrogen-related receptors (ERRs) in health and disease. Biochim Biophys Acta 1812: 10321040. [PMID:21172432]

Deblois G, Giguère V. (2013) Oestrogen-related receptors in breast cancer: control of cellular metabolism and beyond. Nat Rev Cancer 13: 2736. [PMID:23192231]

Germain P, Staels B, Dacquet C, Spedding M, Laudet V. (2006) Overview of nomenclature of nuclear receptors. Pharmacol Rev 58: 685704. [PMID:17132848]

Huang P, Chandra V, Rastinejad F. (2010) Structural overview of the nuclear receptor superfamily: insights into physiology and therapeutics. Annu Rev Physiol 72: 247272. [PMID:20148675]

Hwang-Verslues WW, Sladek FM. (2010) HNF4α–role in drug metabolism and potential drug target?. Curr Opin Pharmacol 10: 698705. [PMID:20833107]

Sladek FM. (2011) What are nuclear receptor ligands?. Mol Cell Endocrinol 334: 313. [PMID:20615454]

  1. Top of page
  2. Abstract
  3. 1A. Thyroid Hormone Receptors
  4. 1B. Retinoic acid receptors
  5. 1C. Peroxisome proliferator-activated receptors
  6. 1D. Rev-Erb receptors
  7. 1F. Retinoic acid-related orphans
  8. 1H. Liver X receptor-like receptors
  9. 1I. Vitamin D receptor-like receptors
  10. 2A. Hepatocyte nuclear factor-4 receptors
  11. 2B. Retinoid X receptors
  12. 2C. Testicular receptors
  13. 2E. Tailless-like receptors
  14. 2F. COUP-TF-like receptors
  15. 3B. Estrogen-related receptors
  16. 4A. Nerve growth factor IB-like receptors
  17. 5A. Fushi tarazu F1-like receptors
  18. 6A. Germ cell nuclear factor receptors
  19. 0B. DAX-like receptors
  20. Steroid hormone receptors
  21. References
Overview

Nerve growth factor IB-like receptors (nomenclature as agreed by NC-IUPHAR committee on nuclear hormone receptors [110]) have yet to be officially paired with an endogenous ligand.

NomenclatureNerve Growth factor IB Nuclear receptor related 1 Neuron-derived orphan receptor 1
Systematic nomenclatureNR4A1NR4A2NR4A3
HGNC, UniProtNR4A1, P22736 NR4A2, P43354 NR4A3, Q92570
CommentAn endogenous agonist, cytosporone B, has been described [113], although structural analysis and molecular modelling has not identified a ligand binding site [109, 111, 112]

Further reading

Benoit G, Cooney A, Giguere V, Ingraham H, Lazar M, Muscat G, Perlmann T, Renaud JP, Schwabe J, Sladek F, Tsai MJ, Laudet V. (2006) International Union of Pharmacology. LXVI. Orphan nuclear receptors. Pharmacol Rev 58: 798836. [PMID:17132856]

Germain P, Staels B, Dacquet C, Spedding M, Laudet V. (2006) Overview of nomenclature of nuclear receptors. Pharmacol Rev 58: 685704. [PMID:17132848]

Huang P, Chandra V, Rastinejad F. (2010) Structural overview of the nuclear receptor superfamily: insights into physiology and therapeutics. Annu Rev Physiol 72: 247272. [PMID:20148675]

McMorrow JP, Murphy EP. (2011) Inflammation: a role for NR4A orphan nuclear receptors?. Biochem Soc Trans 39: 688693. [PMID:21428963]

Mohan HM, Aherne CM, Rogers AC, Baird AW, Winter DC, Murphy EP. (2012) Molecular pathways: the role of NR4A orphan nuclear receptors in cancer. Clin Cancer Res 18: 32233228. [PMID:22566377]

Pearen MA, Muscat GE. (2010) Minireview: Nuclear hormone receptor 4A signaling: implications for metabolic disease. Mol Endocrinol 24: 18911903. [PMID:20392876]

Sladek FM. (2011) What are nuclear receptor ligands?. Mol Cell Endocrinol 334: 313. [PMID:20615454]

van Tiel CM, de Vries CJ. (2012) NR4All in the vessel wall. J Steroid Biochem Mol Biol 130: 186193. [PMID:21277978]

Zhao Y, Bruemmer D. (2010) NR4A orphan nuclear receptors: transcriptional regulators of gene expression in metabolism and vascular biology. Arterioscler Thromb Vasc Biol 30: 15351541. [PMID:20631354]

  1. Top of page
  2. Abstract
  3. 1A. Thyroid Hormone Receptors
  4. 1B. Retinoic acid receptors
  5. 1C. Peroxisome proliferator-activated receptors
  6. 1D. Rev-Erb receptors
  7. 1F. Retinoic acid-related orphans
  8. 1H. Liver X receptor-like receptors
  9. 1I. Vitamin D receptor-like receptors
  10. 2A. Hepatocyte nuclear factor-4 receptors
  11. 2B. Retinoid X receptors
  12. 2C. Testicular receptors
  13. 2E. Tailless-like receptors
  14. 2F. COUP-TF-like receptors
  15. 3B. Estrogen-related receptors
  16. 4A. Nerve growth factor IB-like receptors
  17. 5A. Fushi tarazu F1-like receptors
  18. 6A. Germ cell nuclear factor receptors
  19. 0B. DAX-like receptors
  20. Steroid hormone receptors
  21. References
Overview

Fushi tarazu F1-like receptors (nomenclature as agreed by NC-IUPHAR committee on nuclear hormone receptors [114]) have yet to be officially paired with an endogenous ligand.

NomenclatureSteroidogenic factor 1 Liver receptor homolog-1
Systematic nomenclatureNR5A1NR5A2
HGNC, UniProtNR5A1, Q13285 NR5A2, O00482
CommentReported to be inhibited by AC45594[115] and SID7969543[116]

Further reading

Benoit G, Cooney A, Giguere V, Ingraham H, Lazar M, Muscat G, Perlmann T, Renaud JP, Schwabe J, Sladek F, Tsai MJ, Laudet V. (2006) International Union of Pharmacology. LXVI. Orphan nuclear receptors. Pharmacol Rev 58: 798836. [PMID:17132856]

Büdefeld T, Tobet SA, Majdic G. (2012) Steroidogenic factor 1 and the central nervous system. J Neuroendocrinol 24: 225235. [PMID:21668533]

El-Khairi R, Martinez-Aguayo A, Ferraz-de-Souza B, Lin L, Achermann JC. (2011) Role of DAX-1 (NR0B1) and steroidogenic factor-1 (NR5A1) in human adrenal function. Endocr Dev 20: 3846. [PMID:21164257]

Fernandez-Marcos PJ, Auwerx J, Schoonjans K. (2011) Emerging actions of the nuclear receptor LRH-1 in the gut. Biochim Biophys Acta 1812: 947955. [PMID:21194563]

Ferraz-de-Souza B, Lin L, Achermann JC. (2011) Steroidogenic factor-1 (SF-1, NR5A1) and human disease. Mol Cell Endocrinol 336: 198205. [PMID:21078366]

Germain P, Staels B, Dacquet C, Spedding M, Laudet V. (2006) Overview of nomenclature of nuclear receptors. Pharmacol Rev 58: 685704. [PMID:17132848]

Huang P, Chandra V, Rastinejad F. (2010) Structural overview of the nuclear receptor superfamily: insights into physiology and therapeutics. Annu Rev Physiol 72: 247272. [PMID:20148675]

Lazarus KA, Wijayakumara D, Chand AL, Simpson ER, Clyne CD. (2012) Therapeutic potential of Liver Receptor Homolog-1 modulators. J Steroid Biochem Mol Biol 130: 138146. [PMID:22266285]

Młynarczuk J, Rękawiecki R. (2010) The role of the orphan receptor SF-1 in the development and function of the ovary. Reprod Biol 10: 177193. [PMID:21113200]

Schimmer BP, White PC. (2010) Minireview: steroidogenic factor 1: its roles in differentiation, development, and disease. Mol Endocrinol 24: 13221337. [PMID:20203099]

Sladek FM. (2011) What are nuclear receptor ligands?. Mol Cell Endocrinol 334: 313. [PMID:20615454]

  1. Top of page
  2. Abstract
  3. 1A. Thyroid Hormone Receptors
  4. 1B. Retinoic acid receptors
  5. 1C. Peroxisome proliferator-activated receptors
  6. 1D. Rev-Erb receptors
  7. 1F. Retinoic acid-related orphans
  8. 1H. Liver X receptor-like receptors
  9. 1I. Vitamin D receptor-like receptors
  10. 2A. Hepatocyte nuclear factor-4 receptors
  11. 2B. Retinoid X receptors
  12. 2C. Testicular receptors
  13. 2E. Tailless-like receptors
  14. 2F. COUP-TF-like receptors
  15. 3B. Estrogen-related receptors
  16. 4A. Nerve growth factor IB-like receptors
  17. 5A. Fushi tarazu F1-like receptors
  18. 6A. Germ cell nuclear factor receptors
  19. 0B. DAX-like receptors
  20. Steroid hormone receptors
  21. References
Overview

Germ cell nuclear factor receptors (nomenclature as agreed by NC-IUPHAR committee on nuclear hormone receptors [117]) have yet to be officially paired with an endogenous ligand.

NomenclatureGerm cell nuclear factor
Systematic nomenclatureNR6A1
HGNC, UniProtNR6A1, Q15406

Further reading

Benoit G, Cooney A, Giguere V, Ingraham H, Lazar M, Muscat G, Perlmann T, Renaud JP, Schwabe J, Sladek F, Tsai MJ, Laudet V. (2006) International Union of Pharmacology. LXVI. Orphan nuclear receptors. Pharmacol Rev 58: 798836. [PMID:17132856]

Germain P, Staels B, Dacquet C, Spedding M, Laudet V. (2006) Overview of nomenclature of nuclear receptors. Pharmacol Rev 58: 685704. [PMID:17132848]

Huang P, Chandra V, Rastinejad F. (2010) Structural overview of the nuclear receptor superfamily: insights into physiology and therapeutics. Annu Rev Physiol 72: 247272. [PMID:20148675]

Sladek FM. (2011) What are nuclear receptor ligands?. Mol Cell Endocrinol 334: 313. [PMID:20615454]

  1. Top of page
  2. Abstract
  3. 1A. Thyroid Hormone Receptors
  4. 1B. Retinoic acid receptors
  5. 1C. Peroxisome proliferator-activated receptors
  6. 1D. Rev-Erb receptors
  7. 1F. Retinoic acid-related orphans
  8. 1H. Liver X receptor-like receptors
  9. 1I. Vitamin D receptor-like receptors
  10. 2A. Hepatocyte nuclear factor-4 receptors
  11. 2B. Retinoid X receptors
  12. 2C. Testicular receptors
  13. 2E. Tailless-like receptors
  14. 2F. COUP-TF-like receptors
  15. 3B. Estrogen-related receptors
  16. 4A. Nerve growth factor IB-like receptors
  17. 5A. Fushi tarazu F1-like receptors
  18. 6A. Germ cell nuclear factor receptors
  19. 0B. DAX-like receptors
  20. Steroid hormone receptors
  21. References
Overview

Dax-like receptors (nomenclature as agreed by NC-IUPHAR committee on nuclear hormone receptors [118]) have yet to be officially paired with an endogenous ligand.

NomenclatureDAX1 SHP
Systematic nomenclatureNR0B1 NR0B2
HGNC, UniProtNR0B1, P51843 NR0B2, Q15466

Further reading

Benoit G, Cooney A, Giguere V, Ingraham H, Lazar M, Muscat G, Perlmann T, Renaud JP, Schwabe J, Sladek F, Tsai MJ, Laudet V. (2006) International Union of Pharmacology. LXVI. Orphan nuclear receptors. Pharmacol Rev 58: 798836. [PMID:17132856]

Chanda D, Park JH, Choi HS. (2008) Molecular basis of endocrine regulation by orphan nuclear receptor Small Heterodimer Partner. Endocr J 55: 253268. [PMID:17984569]

Ehrlund A, Treuter E. (2012) Ligand-independent actions of the orphan receptors/corepressors DAX-1 and SHP in metabolism, reproduction and disease. J Steroid Biochem Mol Biol 130: 169179. [PMID:21550402]

El-Khairi R, Martinez-Aguayo A, Ferraz-de-Souza B, Lin L, Achermann JC. (2011) Role of DAX-1 (NR0B1) and steroidogenic factor-1 (NR5A1) in human adrenal function. Endocr Dev 20: 3846. [PMID:21164257]

Germain P, Staels B, Dacquet C, Spedding M, Laudet V. (2006) Overview of nomenclature of nuclear receptors. Pharmacol Rev 58: 685704. [PMID:17132848]

Huang P, Chandra V, Rastinejad F. (2010) Structural overview of the nuclear receptor superfamily: insights into physiology and therapeutics. Annu Rev Physiol 72: 247272. [PMID:20148675]

Młynarczuk J, Rękawiecki R. (2010) The role of the orphan receptor SF-1 in the development and function of the ovary. Reprod Biol 10: 177193. [PMID:21113200]

Sladek FM. (2011) What are nuclear receptor ligands?. Mol Cell Endocrinol 334: 313. [PMID:20615454]

Zhang Y, Hagedorn CH, Wang L. (2011) Role of nuclear receptor SHP in metabolism and cancer. Biochim Biophys Acta 1812: 893908. [PMID:20970497]

  1. Top of page
  2. Abstract
  3. 1A. Thyroid Hormone Receptors
  4. 1B. Retinoic acid receptors
  5. 1C. Peroxisome proliferator-activated receptors
  6. 1D. Rev-Erb receptors
  7. 1F. Retinoic acid-related orphans
  8. 1H. Liver X receptor-like receptors
  9. 1I. Vitamin D receptor-like receptors
  10. 2A. Hepatocyte nuclear factor-4 receptors
  11. 2B. Retinoid X receptors
  12. 2C. Testicular receptors
  13. 2E. Tailless-like receptors
  14. 2F. COUP-TF-like receptors
  15. 3B. Estrogen-related receptors
  16. 4A. Nerve growth factor IB-like receptors
  17. 5A. Fushi tarazu F1-like receptors
  18. 6A. Germ cell nuclear factor receptors
  19. 0B. DAX-like receptors
  20. Steroid hormone receptors
  21. References
Overview

Steroid hormone receptors (nomenclature as agreed by NC-IUPHAR Committee on Nuclear Receptors, [120, 132]) are nuclear hormone receptors of the NR3 class, with endogenous agonists that may be divided into 3-hydroxysteroids (estrone and 17β-estradiol) and 3-ketosteroids (dihydrotestosterone [DHT], aldosterone, cortisol, corticosterone, progesterone and testosterone). These receptors exist as dimers coupled with chaperone molecules (such as hsp90 (HSP90AB1, P08238) and immunophilin FKBP52:FKBP4, Q02790), which are shed on binding the steroid hormone. Although rapid signalling phenomena are observed [130, 138], the principal signalling cascade appears to involve binding of the activated receptors to nuclear hormone response elements of the genome, with a 15-nucleotide consensus sequence AGAACAnnnTGTTCT (i.e. an inverted palindrome) as homo- or heterodimers. They also affect transcription by protein–protein interactions with other transcription factors, such as activator protein 1 (AP-1) and nuclear factor κB (NF-κB). Splice variants of each of these receptors can form functional or non-functional monomers that can dimerize to form functional or non-functional receptors. For example, alternative splicing of PR mRNA produces A and B monomers that combine to produce functional AA, AB and BB receptors with distinct characteristics [148].

A 7TM receptor responsive to estrogen (GPER1, Q99527, also known as GPR30, see [137]) has been described. Human orthologues of 7TM ‘membrane progestin receptors’ (PAQR7, PAQR8 and PAQR5), initially discovered in fish [151, 152], appear to localize to intracellular membranes and respond to ‘non-genomic’ progesterone analogues independently of G proteins [142].

3A. Estrogen receptors

NomenclatureEstrogen receptor-α Estrogen receptor-β
Systematic nomenclatureNR3A1NR3A2
HGNC, UniProtESR1, P03372 ESR2, Q92731
Selective agonists (pKi)PPT (9.64) [128, 143]ERB 041[133], diarylpropionitril (8.6) [135, 143], WAY200070 (pIC50 8.52 – 9.0) [133]
Selective antagonists (pKi)methyl-piperidino-pyrazole (8.57) [145]PHTPP[119], R,R-THC (8.44) [134, 146]
Comments

R,R-THC exhibits partial agonist activity at ERα [134, 146]. Estrogen receptors may be blocked non-selectively by tamoxifen and raloxifene and labelled by [3H]17β-estradiol and [3H]tamoxifen. Many agents thought initially to be antagonists at estrogen receptors appear to have tissue-specific efficacy (e.g. tamoxifen is an antagonist at estrogen receptors in the breast, but is an agonist at estrogen receptors in the uterus), hence the descriptor SERM (selective estrogen receptor modulator) or SnuRM (selective nuclear receptor modulator). Y134 has been suggested to be an ERα-selective estrogen receptor modulator [136].

3C. 3-Ketosteroid receptors

NomenclatureAndrogen receptor Glucocorticoid receptor Mineralocorticoid receptor Progesterone receptor
Systematic nomenclatureNR3C4NR3C1NR3C2NR3C3
HGNC, UniProtAR, P10275 NR3C1, P04150 NR3C2, P08235 PGR, P06401
Rank order of potencydihydrotestosterone>testosterone cortisol,corticosterone>>aldosterone,deoxycortisone[139]corticosterone,cortisol,aldosterone,progesterone[139]progesterone
Endogenous agonists (pKi)dihydrotestosterone (pKd 9.3) [147]aldosterone (Selective) (pIC50 9.8 – 10.0) [126, 139]progesterone (Selective)
Selective agonists (pKi)methyltrienolone (pEC50 < 5.0) [149], mibolerone (pIC50 8.96) [124]fluticasone, RU26988, RU28362 levonorgestrel[140], ORG2058
Selective antagonists (pKi)hydroxyflutamide (pEC50 6.6) [149], PF0998425 (pIC50 7.1 – 7.5) [131], nilutamide (pIC50 7.07 – 7.12) [141]onapristone, ZK112993, mifepristone (pKd 9.4) [125, 139]onapristone, RU28318, ZK112993, eplerenone (pIC50 1.0) [121, 127]mifepristone, onapristone, ZK112993
Radioligands (Kd)[3H]dihydrotestosterone (Agonist), [3H]mibolerone (Agonist), [3H]R1881 (Agonist)[3H]dexamethasone (Agonist)[3H]aldosterone (Agonist) (3x10-10 – 4x10-10 M - Rat) [123, 144][3H]ORG2058 (Agonist)
Comments

[3H]dexamethasone also binds to MR in vitro. PR antagonists have been suggested to subdivide into Type I (e.g. onapristone) and Type II (e.g. ZK112993) groups. These groups appear to promote binding of PR to DNA with different efficacies and evoke distinct conformational changes in the receptor, leading to a transcription-neutral complex [122, 129]. Mutations in AR underlie testicular feminization and androgen insensibility syndromes, spinal and bulbar muscular atrophy (Kennedy's disease).

Further reading

Blaustein JD. (2008) Progesterone and progestin receptors in the brain: the neglected ones. Endocrinology 149: 27372738. [PMID:18436712]

Briet M, Schiffrin EL. (2010) Aldosterone: effects on the kidney and cardiovascular system. Nat Rev Nephrol 6: 261273. [PMID:20234356]

Brinton RD. (2009) Estrogen-induced plasticity from cells to circuits: predictions for cognitive function. Trends Pharmacol Sci 30: 212222. [PMID:19299024]

Callewaert F, Boonen S, Vanderschueren D. (2010) Sex steroids and the male skeleton: a tale of two hormones. Trends Endocrinol Metab 21: 8995. [PMID:19837603]

Chen Y, Sawyers CL, Scher HI. (2008) Targeting the androgen receptor pathway in prostate cancer. Curr Opin Pharmacol 8: 440448. [PMID:18674639]

Dahlman-Wright K, Cavailles V, Fuqua SA, Jordan VC, Katzenellenbogen JA, Korach KS, Maggi A, Muramatsu M, Parker MG, Gustafsson JA. (2006) International Union of Pharmacology. LXIV. Estrogen receptors. Pharmacol Rev 58: 773781. [PMID:17132854]

Feldman RD, Gros R. (2011) Unraveling the mechanisms underlying the rapid vascular effects of steroids: sorting out the receptors and the pathways. Br J Pharmacol 163: 11631169. [PMID:21545416]

Gross KL, Cidlowski JA. (2008) Tissue-specific glucocorticoid action: a family affair. Trends Endocrinol Metab 19: 331339. [PMID:18805703]

Hadoke PW, Iqbal J, Walker BR. (2009) Therapeutic manipulation of glucocorticoid metabolism in cardiovascular disease. Br J Pharmacol 156: 689712. [PMID:19239478]

Handelsman DJ. (2008) Indirect androgen doping by oestrogen blockade in sports. Br J Pharmacol 154: 598605. [PMID:18500381]

Joëls M, Karst H, DeRijk R, de Kloet ER. (2008) The coming out of the brain mineralocorticoid receptor. Trends Neurosci 31: 17. [PMID:18063498]

Kellner M, Wiedemann K. (2008) Mineralocorticoid receptors in brain, in health and disease: possibilities for new pharmacotherapy. Eur J Pharmacol 583: 372378. [PMID:18272147]

Kerkhofs S, Denayer S, Haelens A, Claessens F. (2009) Androgen receptor knockout and knock-in mouse models. J Mol Endocrinol 42: 1117. [PMID:18923000]

Lange CA, Gioeli D, Hammes SR, Marker PC. (2007) Integration of rapid signaling events with steroid hormone receptor action in breast and prostate cancer. Annu Rev Physiol 69: 171199. [PMID:17037979]

Levin ER. (2008) Rapid signaling by steroid receptors. Am J Physiol Regul Integr Comp Physiol 295: R1425R1430. [PMID:18784332]

Lu NZ, Wardell SE, Burnstein KL, Defranco D, Fuller PJ, Giguere V, Hochberg RB, McKay L, Renoir JM, Weigel NL, Wilson EM, McDonnell DP, Cidlowski JA. (2006) International Union of Pharmacology. LXV. The pharmacology and classification of the nuclear receptor superfamily: glucocorticoid, mineralocorticoid, progesterone, and androgen receptors. Pharmacol Rev 58: 782797. [PMID:17132855]

Matsumoto T, Shiina H, Kawano H, Sato T, Kato S. (2008) Androgen receptor functions in male and female physiology. J Steroid Biochem Mol Biol 109: 236241. [PMID:18434134]

Mohler ML, Bohl CE, Jones A, Coss CC, Narayanan R, He Y, Hwang DJ, Dalton JT, Miller DD. (2009) Nonsteroidal selective androgen receptor modulators (SARMs): dissociating the anabolic and androgenic activities of the androgen receptor for therapeutic benefit. J Med Chem 52: 35973617. [PMID:19432422]

Pippal JB, Fuller PJ. (2008) Structure-function relationships in the mineralocorticoid receptor. J Mol Endocrinol 41: 405413. [PMID:18805937]

Prossnitz ER, Arterburn JB, Smith HO, Oprea TI, Sklar LA, Hathaway HJ. (2008) Estrogen signaling through the transmembrane G protein-coupled receptor GPR30. Annu Rev Physiol 70: 165190. [PMID:18271749]

Schumacher M, Sitruk-Ware R, De Nicola AF. (2008) Progesterone and progestins: neuroprotection and myelin repair. Curr Opin Pharmacol 8: 740746. [PMID:18929681]

Simons SS. (2010) Glucocorticoid receptor cofactors as therapeutic targets. Curr Opin Pharmacol 10: 613619. [PMID:20801081]

Taplin ME. (2007) Drug insight: role of the androgen receptor in the development and progression of prostate cancer. Nat Clin Pract Oncol 4: 236244. [PMID:17392714]

Weiser MJ, Foradori CD, Handa RJ. (2008) Estrogen receptor beta in the brain: from form to function. Brain Res Rev 57: 309320. [PMID:17662459]

Woolley CS. (2007) Acute effects of estrogen on neuronal physiology. Annu Rev Pharmacol Toxicol 47: 657680. [PMID:16918306]

References

  1. Top of page
  2. Abstract
  3. 1A. Thyroid Hormone Receptors
  4. 1B. Retinoic acid receptors
  5. 1C. Peroxisome proliferator-activated receptors
  6. 1D. Rev-Erb receptors
  7. 1F. Retinoic acid-related orphans
  8. 1H. Liver X receptor-like receptors
  9. 1I. Vitamin D receptor-like receptors
  10. 2A. Hepatocyte nuclear factor-4 receptors
  11. 2B. Retinoid X receptors
  12. 2C. Testicular receptors
  13. 2E. Tailless-like receptors
  14. 2F. COUP-TF-like receptors
  15. 3B. Estrogen-related receptors
  16. 4A. Nerve growth factor IB-like receptors
  17. 5A. Fushi tarazu F1-like receptors
  18. 6A. Germ cell nuclear factor receptors
  19. 0B. DAX-like receptors
  20. Steroid hormone receptors
  21. References