Stephen Ph Alexander1, John A Cidlowski2, Eamonn Kelly3, Alistair Mathie4, John A Peters5, Emma L Veale4, Jane F Armstrong6, Elena Faccenda6, Simon D Harding6, Adam J Pawson6, Christopher Southan5, Jamie A Davies6, Laurel Coons7, Peter J Fuller8, Kenneth S Korach9, Morag J Young10. 1. School of Life Sciences, University of Nottingham Medical School, Nottingham, NG7 2UH, UK. 2. National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC, 27709, USA. 3. School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, BS8 1TD, UK. 4. Medway School of Pharmacy, The Universities of Greenwich and Kent at Medway, Anson Building, Central Avenue, Chatham Maritime, Chatham, Kent, ME4 4TB, UK. 5. Neuroscience Division, Medical Education Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK. 6. Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, EH8 9XD, UK. 7. Duke University Medical Center, Durham, NC, USA. 8. Hudson Institute of Medical Research, Clayton, Australia. 9. National Institute of Health, Research Triangle Park, NC, USA. 10. Monash University, Melbourne, Australia.
Abstract
The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15540. Nuclear hormone receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein-coupled receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.
The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15540. Nuclear hormone receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein-coupled receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.
The authors state that there are no conflicts of interest to disclose.
Overview
Nuclear 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 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 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 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.
Thyroid hormone receptors (TRs, nomenclature as agreed by the
Subcommittee on Nuclear Hormone Receptors [
,
]) are nuclear hormone receptors of the NR1A family, with diverse roles regulating macronutrient metabolism, cognition and cardiovascular homeostasis. TRs are activated by thyroxine (T) and thyroid hormone (triiodothyronine). 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 [108].
Further reading on 1A. Thyroid hormone receptors
Elbers LP et al. (2016) Thyroid Hormone Mimetics: the Past, Current Status and Future Challenges. Curr Atheroscler Rep
18: 14 [PMID:26886134]Flamant F et al. (2006) International Union of Pharmacology. LIX. The pharmacology and classification of the nuclear receptor superfamily: thyroid hormone receptors. Pharmacol Rev
58: 705‐11 [PMID:17132849]Mendoza A et al. (2017) New insights into thyroid hormone action. Pharmacol Ther
173: 135‐145 [PMID:28174093]
Comments
An interaction with integrin αVβ3 has been suggested to underlie plasma membrane localization of TRs and non‐genomic signalling [8].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.
1B. Retinoic acid receptors
Retinoic acid receptors (nomenclature as agreed by the
Subcommittee on Nuclear Hormone Receptors [
,
]) are nuclear hormone receptors of the NR1B family activated by the vitamin A‐derived agonists tretinoin (ATRA) and alitretinoin, and the RAR‐selective synthetic agonists TTNPB and adapalene. BMS493 is a family‐selective antagonist [48].
Further reading on 1B. Retinoic acid receptors
Duong V et al. (2011) The molecular physiology of nuclear retinoic acid receptors. From health to disease. Biochim Biophys Acta
1812: 1023‐31 [PMID:20970498]Germain P et al. (2006) International Union of Pharmacology. LX. Retinoic acid receptors. Pharmacol Rev
58: 712‐25 [PMID:17132850]Larange A et al. (2016) Retinoic Acid and Retinoic Acid Receptors as Pleiotropic Modulators of the Immune System. Annu Rev Immunol
34: 369‐94 [PMID:27168242]Saeed A et al. (2017) The interrelationship between bile acid and vitamin A homeostasis. Biochim Biophys Acta
1862: 496‐512 [PMID:28111285]Ro 41‐5253 has been suggested to be a PPARγ agonist [127]. LE135 is an antagonist with selectivity for RARα and RARβ compared with RARγ [83].
1C. Peroxisome proliferator‐activated receptors
Peroxisome proliferator‐activated receptors (PPARs, nomenclature as agreed by the
Subcommittee on Nuclear Hormone Receptors [
,
]) 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 [13, 99], including 15‐deoxy‐Δ, prostacyclin (PGI), many fatty acids and their oxidation products, lysophosphatidic acid (LPA) [96], 13‐HODE, 15S‐HETE, Paz‐PC, azelaoyl‐PAF and leukotriene B4 (LTB). Bezafibrate acts as a non‐selective agonist for the PPAR family [155]. 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.
Further reading on 1C. Peroxisome proliferator‐activated receptors
Cheang WS et al. (2015) The peroxisome proliferator‐activated receptors in cardiovascular diseases: experimental benefits and clinical challenges. Br J Pharmacol
172: 5512‐22 [PMID:25438608]Gross B et al. (2017) PPARs in obesity‐induced T2DM, dyslipidaemia and NAFLD. Nat Rev Endocrinol
13: 36‐49 [PMID:27636730]Hallenborg P et al. (2016) The elusive endogenous adipogenic PPARγ agonists: Lining up the suspects. Prog Lipid Res
61: 149‐62 [PMID:26703188]Michalik L et al. (2006) International Union of Pharmacology. LXI. Peroxisome proliferator‐activated receptors. Pharmacol Rev
58: 726‐41 [PMID:17132851]Sauer S. (2015) Ligands for the Nuclear Peroxisome Proliferator‐Activated Receptor Gamma. Trends Pharmacol Sci
36: 688‐704 [PMID:26435213]As with the estrogen receptor antagonists, many agents show tissue‐selective efficacy (e.g. [12, 107, 122]). Agonists with mixed activity at PPARα and PPARγ have also been described (e.g [32, 54, 159]).
1D. Rev‐Erb receptors
Rev‐erb receptors (nomenclature as agreed by the
Subcommittee on Nuclear Hormone Receptors [
,
]) have yet to be officially paired with an endogenous ligand, but are thought to be activated by heme.
Further reading on 1D. Rev‐Erb receptors
Benoit G et al. (2006) International Union of Pharmacology. LXVI. Orphan nuclear receptors. Pharmacol Rev
58: 798‐836 [PMID:17132856]Gonzalez‐Sanchez E et al. (2015) Nuclear receptors in acute and chronic cholestasis. Dig Dis
33: 357‐66 [PMID:26045270]Gustafson CL et al. (2015) Emerging models for the molecular basis of mammalian circadian timing. Biochemistry
54: 134‐49 [PMID:25303119]Sousa EH et al. (2017) Drug discovery targeting heme‐based sensors and their coupled activities. J Inorg Biochem
167: 12‐20 [PMID:27893989]
1F. Retinoic acid‐related orphans
Retinoic acid receptor‐related orphan receptors (ROR, nomenclature as agreed by the
Subcommittee on Nuclear Hormone Receptors [
,
]) have yet to be assigned a definitive endogenous ligand, although RORα may be synthesized with a ‘captured’ agonist such as cholesterol [64, 65].
Further reading on 1F. Retinoic acid‐related orphans
Benoit G et al. (2006) International Union of Pharmacology. LXVI. Orphan nuclear receptors. Pharmacol Rev
58: 798‐836 [PMID:17132856]Cyr P et al. (2016) Recent progress on nuclear receptor RORγ modulators. Bioorg Med Chem Lett
26: 4387‐4393 [PMID:27542308]Germain P et al. (2006) Overview of nomenclature of nuclear receptors. Pharmacol Rev
58: 685‐704 [PMID:17132848]Guillemot‐Legris O et al. (2016) Oxysterols in Metabolic Syndrome: From Bystander Molecules to Bioactive Lipids. Trends Mol Med
22: 594‐614 [PMID:27286741]Mutemberezi V et al. (2016) Oxysterols: From cholesterol metabolites to key mediators. Prog Lipid Res
64: 152‐169 [PMID:27687912]Tretinoin shows selectivity for RORβ within the ROR family [134]. RORα has been suggested to be a nuclear receptor responding to melatonin[154].
1H. Liver X receptor‐like receptors
Liver X and farnesoid X receptors (LXR and FXR, nomenclature as agreed by the
Subcommittee on Nuclear Hormone Receptors [
,
]) are members of a steroid analogue‐activated nuclear receptor subfamily, 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. In humans and primates, NR1H5P is a pseudogene. However, in other mammals, it encodes a functional nuclear hormone receptor that appears to be involved in cholesterol biosynthesis [111].
Further reading on 1H. Liver X receptor‐like receptors
Courtney R et al. (2016) LXR Regulation of Brain Cholesterol: From Development to Disease. Trends Endocrinol Metab
27: 404‐414 [PMID:27113081]El‐Gendy BEM et al. (2018) Recent Advances in the Medicinal Chemistry of Liver X Receptors. J Med Chem
61: 10935‐10956 [PMID:30004226]Gadaleta RM et al. (2010) Bile acids and their nuclear receptor FXR: Relevance for hepatobiliary and gastrointestinal disease. Biochim Biophys Acta
1801: 683‐92 [PMID:20399894]Merlen G et al. (2017) Bile acids and their receptors during liver regeneration: "Dangerous protectors". Mol Aspects Med
56: 25‐33 [PMID:28302491]Moore DD et al. (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: 742‐59 [PMID:17132852]Mouzat K et al. (2016) Liver X receptors: from cholesterol regulation to neuroprotection‐a new barrier against neurodegeneration in amyotrophic lateral sclerosis? Cell Mol Life Sci
73: 3801‐8 [PMID:27510420]Schulman IG. (2017) Liver X receptors link lipid metabolism and inflammation. FEBS Lett
591: 2978‐2991 [PMID:28555747]T0901317[120] and GW3965[25] are synthetic agonists acting at both LXRα and LXRβ with less than 10‐fold selectivity.
1I. Vitamin D receptor‐like receptors
Vitamin D (VDR), Pregnane X (PXR) and Constitutive Androstane (CAR) receptors (nomenclature as agreed by the
Subcommittee on Nuclear Hormone Receptors [
,
]) 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 [103].
Further reading on 1I. Vitamin D receptor‐like receptors
Benoit G et al. (2006) International Union of Pharmacology. LXVI. Orphan nuclear receptors. Pharmacol Rev
58: 798‐836 [PMID:17132856]Long MD et al. (2015) Vitamin D receptor and RXR in the post‐genomic era. J Cell Physiol
230: 758‐66 [PMID:25335912]Moore DD et al. (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: 742‐59 [PMID:17132852]
2A. Hepatocyte nuclear factor‐4 receptors
The nomenclature of hepatocyte nuclear factor‐4 receptors is agreed by the
Subcommittee on Nuclear Hormone Receptors [
,
]. While linoleic acid has been identified as the endogenous ligand for HNF4α its function remains ambiguous [163]. HNF4γ has yet to be paired with an endogenous ligand.
Further reading on 2A. Hepatocyte nuclear factor‐4 receptors
Benoit G et al. (2006) International Union of Pharmacology. LXVI. Orphan nuclear receptors. Pharmacol Rev
58: 798‐836 [PMID:17132856]Garattini E et al. (2016) Lipid‐sensors, enigmatic‐orphan and orphan nuclear receptors as therapeutic targets in breast‐cancer. Oncotarget
7: 42661‐42682 [PMID:26894976]Germain P et al. (2006) Overview of nomenclature of nuclear receptors. Pharmacol Rev
58: 685‐704 [PMID:17132848]Lu H. (2016) Crosstalk of HNF4α with extracellular and intracellular signaling pathways in the regulation of hepatic metabolism of drugs and lipids. Acta Pharm Sin B
6: 393‐408 [PMID:27709008]Walesky C et al. (2015) Role of hepatocyte nuclear factor 4α (HNF4α) in cell proliferation and cancer. Gene Expr
16: 101‐8 [PMID:25700366]
2B. Retinoid X receptors
Retinoid X receptors (nomenclature as agreed by the
Subcommittee on Nuclear Hormone Receptors [
,
]) are NR2B family members activated by alitretinoin and the RXR‐selective agonists bexarotene and LG100268, sometimes referred to as rexinoids. UVI3003[106] and HX531 [36] have been described as a pan‐RXR antagonists. These receptors form RXR‐RAR heterodimers and RXR‐RXR homodimers [21, 94].
Further reading on 2B. Retinoid X receptors
Germain P et al. (2006) International Union of Pharmacology. LXIII. Retinoid X receptors. Pharmacol Rev
58: 760‐72 [PMID:17132853]Long MD et al. (2015) Vitamin D receptor and RXR in the post‐genomic era. J Cell Physiol
230: 758‐66 [PMID:25335912]Menéndez‐Gutiérrez MP et al. (2017) The multi‐faceted role of retinoid X receptor in bone remodeling. Cell Mol Life Sci
74: 2135‐2149 [PMID:28105491]
2C. Testicular receptors
Testicular receptors (nomenclature as agreed by the
Subcommittee on Nuclear Hormone Receptors [
]) have yet to be officially paired with an endogenous ligand, although testicular receptor 4 has been reported to respond to retinoids.
Further reading on 2C. Testicular receptors
Benoit G et al. (2006) International Union of Pharmacology. LXVI. Orphan nuclear receptors. Pharmacol Rev
58: 798‐836 [PMID:17132856]Germain P et al. (2006) Overview of nomenclature of nuclear receptors. Pharmacol Rev
58: 685‐704 [PMID:17132848]Safe S et al. (2014) Minireview: role of orphan nuclear receptors in cancer and potential as drug targets. Mol Endocrinol
28: 157‐72 [PMID:24295738]Wu D et al. (2016) The emerging roles of orphan nuclear receptors in prostate cancer. Biochim Biophys Acta
1866: 23‐36 [PMID:27264242]
2E. Tailless‐like receptors
Tailless‐like receptors (nomenclature as agreed by the
Subcommittee on Nuclear Hormone Receptors [
]) have yet to be officially paired with an endogenous ligand.
Further reading on 2E. Tailless‐like receptors
Benod C et al. (2016) TLX: An elusive receptor. J Steroid Biochem Mol Biol
157: 41‐7 [PMID:26554934]Benoit G et al. (2006) International Union of Pharmacology. LXVI. Orphan nuclear receptors. Pharmacol Rev
58: 798‐836 [PMID:17132856]Germain P et al. (2006) Overview of nomenclature of nuclear receptors. Pharmacol Rev
58: 685‐704 [PMID:17132848]O'Leary JD et al. (2018) Regulation of behaviour by the nuclear receptor TLX. Genes Brain Behav
17: e12357 [PMID:27790850]
2F. COUP‐TF‐like receptors
COUP‐TF‐like receptors (nomenclature as agreed by the
Subcommittee on Nuclear Hormone Receptors [
,
]) have yet to be officially paired with an endogenous ligand.
Further reading on 2F. COUP‐TF‐like receptors
Benoit G et al. (2006) International Union of Pharmacology. LXVI. Orphan nuclear receptors. Pharmacol Rev
58: 798‐836 [PMID:17132856]Germain P et al. (2006) Overview of nomenclature of nuclear receptors. Pharmacol Rev
58: 685‐704 [PMID:17132848]Wu D et al. (2016) The emerging roles of orphan nuclear receptors in prostate cancer. Biochim Biophys Acta
1866: 23‐36 [PMID:27264242]Wu SP et al. (2016) Choose your destiny: Make a cell fate decision with COUP‐TFII. J Steroid Biochem Mol Biol
157: 7‐12 [PMID:26658017]
3B. Estrogen‐related receptors
Estrogen‐related receptors (nomenclature as agreed by the
Subcommittee on Nuclear Hormone Receptors [
]) have yet to be officially paired with an endogenous ligand.
Further reading on 3B. Estrogen‐related receptors
Benoit G et al. (2006) International Union of Pharmacology. LXVI. Orphan nuclear receptors. Pharmacol Rev
58: 798‐836 [PMID:17132856]Divekar SD et al. (2016) Estrogen‐related receptor β (ERRβ) ‐ renaissance receptor or receptor renaissance? Nucl Recept Signal
14: e002 [PMID:27507929]Germain P et al. (2006) Overview of nomenclature of nuclear receptors. Pharmacol Rev
58: 685‐704 [PMID:17132848]Tam IS et al. (2016) There and back again: The journey of the estrogen‐related receptors in the cancer realm. J Steroid Biochem Mol Biol
157: 13‐9 [PMID:26151739]Wu D et al. (2016) The emerging roles of orphan nuclear receptors in prostate cancer. Biochim Biophys Acta
1866: 23‐36 [PMID:27264242]
4A. Nerve growth factor IB‐like receptors
Nerve growth factor IB‐like receptors (nomenclature as agreed by the
Subcommittee on Nuclear Hormone Receptors [
]) have yet to be officially paired with an endogenous ligand.
Further reading on 4A. Nerve growth factor IB‐like receptors
Benoit G et al. (2006) International Union of Pharmacology. LXVI. Orphan nuclear receptors. Pharmacol Rev
58: 798‐836 [PMID:17132856]Germain P et al. (2006) Overview of nomenclature of nuclear receptors. Pharmacol Rev
58: 685‐704 [PMID:17132848]Ranhotra HS. (2015) The NR4A orphan nuclear receptors: mediators in metabolism and diseases. J Recept Signal Transduct Res
35: 184‐8 [PMID:25089663]Rodríguez‐Calvo R et al. (2017) The NR4A subfamily of nuclear receptors: potential new therapeutic targets for the treatment of inflammatory diseases. Expert Opin Ther Targets
21: 291‐304 [PMID:28055275]Safe S et al. (2016) Nuclear receptor 4A (NR4A) family ‐ orphans no more. J Steroid Biochem Mol Biol
157: 48‐60 [PMID:25917081]
5A. Fushi tarazu F1‐like receptors
Fushi tarazu F1‐like receptors (nomenclature as agreed by the
Subcommittee on Nuclear Hormone Receptors [
]) have yet to be officially paired with an endogenous ligand.
Further reading on 5A. Fushi tarazu F1‐like receptors
Benoit G et al. (2006) International Union of Pharmacology. LXVI. Orphan nuclear receptors. Pharmacol Rev
58: 798‐836 [PMID:17132856]Garattini E et al. (2016) Lipid‐sensors, enigmatic‐orphan and orphan nuclear receptors as therapeutic targets in breast‐cancer. Oncotarget
7: 42661‐42682 [PMID:26894976]Germain P et al. (2006) Overview of nomenclature of nuclear receptors. Pharmacol Rev
58: 685‐704 [PMID:17132848]Zhi X et al. (2016) Structures and regulation of non‐X orphan nuclear receptors: A retinoid hypothesis. J Steroid Biochem Mol Biol
157: 27‐40 [PMID:26159912]Zimmer V et al. (2015) Nuclear receptor variants in liver disease. Dig Dis
33: 415‐9 [PMID:26045277]
6A. Germ cell nuclear factor receptors
Germ cell nuclear factor receptors (nomenclature as agreed by the
Subcommittee on Nuclear Hormone Receptors [
]) have yet to be officially paired with an endogenous ligand.
Further reading on 6A. Germ cell nuclear factor receptors
Benoit G et al. (2006) International Union of Pharmacology. LXVI. Orphan nuclear receptors. Pharmacol Rev
58: 798‐836 [PMID:17132856]Garattini E et al. (2016) Lipid‐sensors, enigmatic‐orphan and orphan nuclear receptors as therapeutic targets in breast‐cancer. Oncotarget
7: 42661‐42682 [PMID:26894976]Germain P et al. (2006) Overview of nomenclature of nuclear receptors. Pharmacol Rev
58: 685‐704 [PMID:17132848]Safe S et al. (2014) Minireview: role of orphan nuclear receptors in cancer and potential as drug targets. Mol Endocrinol
28: 157‐72 [PMID:24295738]Zhi X et al. (2016) Structures and regulation of non‐X orphan nuclear receptors: A retinoid hypothesis. J Steroid Biochem Mol Biol
157: 27‐40 [PMID:26159912]
0B. DAX‐like receptors
Dax‐like receptors (nomenclature as agreed by the
Subcommittee on Nuclear Hormone Receptors [
]) have yet to be officially paired with an endogenous ligand.
Further reading on 0B. DAX‐like receptors
Benoit G et al. (2006) International Union of Pharmacology. LXVI. Orphan nuclear receptors. Pharmacol Rev
58: 798‐836 [PMID:17132856]Garattini E et al. (2016) Lipid‐sensors, enigmatic‐orphan and orphan nuclear receptors as therapeutic targets in breast‐cancer. Oncotarget
7: 42661‐42682 [PMID:26894976]Germain P et al. (2006) Overview of nomenclature of nuclear receptors. Pharmacol Rev
58: 685‐704 [PMID:17132848]Safe S et al. (2014) Minireview: role of orphan nuclear receptors in cancer and potential as drug targets. Mol Endocrinol
28: 157‐72 [PMID:24295738]Wu D et al. (2016) The emerging roles of orphan nuclear receptors in prostate cancer. Biochim Biophys Acta
1866: 23‐36 [PMID:27264242]
Steroid hormone receptors
Steroid hormone receptors (nomenclature as agreed by the
Subcommittee on Nuclear Hormone Receptors [
,
,
]) 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 hsp90β(
, P08238) and immunophilin FKBP52:
, Q02790), which are shed on binding the steroid hormone. Although rapid signalling phenomena are observed [82, 117], 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 [145].A 7TM receptor responsive to estrogen (
, Q99527, also known as GPR30, see [116]) has been described. Human orthologues of 7TM 'membrane progestin receptors' (
,
and
), initially discovered in fish [170, 171], appear to localize to intracellular membranes and respond to 'non‐genomic' progesterone analogues independently of G proteins [132].
3A. Estrogen receptors
Estrogen receptor (ER) activity regulates diverse physiological processes via transcriptional modulation of target genes [1]. The selection of target genes and the magnitude of the response, be it induction or repression, are determined by many factors, including the effect of the hormone ligand and DNA binding on ER structural conformation, and the local cellular regulatory environment. The cellular environment defines the specific complement of DNA enhancer and promoter elements present and the availability of coregulators to form functional transcription complexes. Together, these determinants control the resulting biological response.
Further reading on 3A. Estrogen receptors
Coons LA et al. (2017) DNA Sequence Constraints Define Functionally Active Steroid Nuclear Receptor Binding Sites in Chromatin. Endocrinology
158: 3212‐3234 [PMID:28977594]Dahlman‐Wright K et al. (2006) International Union of Pharmacology. LXIV. Estrogen receptors. Pharmacol Rev
58: 773‐81 [PMID:17132854]Gonzalez‐Sanchez E et al. (2015) Nuclear receptors in acute and chronic cholestasis. Dig Dis
33: 357‐66 [PMID:26045270]Hewitt SC et al. (2016) What's new in estrogen receptor action in the female reproductive tract. J Mol Endocrinol
56: R55‐71 [PMID:26826253]Jameera Begam A et al. (2017) Estrogen receptor agonists/antagonists in breast cancer therapy: A critical review. Bioorg Chem
71: 257‐274 [PMID:28274582]Warner M et al. (2017) Estrogen Receptor β as a Pharmaceutical Target. Trends Pharmacol Sci
38: 92‐99 [PMID:27979317]R,R‐THC exhibits partial agonist activity at ERα [97, 138]. Estrogen receptors may be blocked non‐selectively by tamoxifen and raloxifene and labelled by [ and [. 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 [109].
3C. 3‐Ketosteroid receptors
Steroid hormone receptors (nomenclature as agreed by the
Subcommittee on Nuclear Hormone Receptors [
,
,
]) 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). For rodent GR and MR, the physiological ligand is corticosterone rather than cortisol.
Further reading on 3C. 3‐Ketosteroid receptors
Baker ME et al. (2017) 30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Evolution of the mineralocorticoid receptor: sequence, structure and function. J Endocrinol
234: T1‐T16 [PMID:28468932]Carroll JS et al. (2017) Deciphering the divergent roles of progestogens in breast cancer. Nat Rev Cancer
17: 54‐64 [PMID:27885264]Cohen DM et al. (2017) Nuclear Receptor Function through Genomics: Lessons from the Glucocorticoid Receptor. Trends Endocrinol Metab
28: 531‐540 [PMID:28495406]de Kloet ER et al. (2017) Brain mineralocorticoid receptor function in control of salt balance and stress‐adaptation. Physiol Behav
178: 13‐20 [PMID:28089704]Garg D et al. (2017) Progesterone‐Mediated Non‐Classical Signaling. Trends Endocrinol Metab
28: 656‐668 [PMID:28651856]Lu NZ et al. (2006) International Union of Pharmacology. LXV. The pharmacology and classification of the nuclear receptor superfamily: glucocorticoid, mineralocorticoid, progesterone, and androgen receptors. Pharmacol Rev
58: 782‐97 [PMID:17132855]Lucas‐Herald AK et al. (2017) Genomic and non‐genomic effects of androgens in the cardiovascular system: clinical implications. Clin Sci
131: 1405‐1418 [PMID:28645930]Wadosky KM et al. (2017) Androgen receptor splice variants and prostate cancer: From bench to bedside. Oncotarget
8: 18550‐18576 [PMID:28077788]Weikum ER et al. (2017) Glucocorticoid receptor control of transcription: precision and plasticity via allostery. Nat Rev Mol Cell Biol
18: 159‐174 [PMID:28053348][ 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 [43, 81]. Mutations in AR underlie testicular feminization and androgen insensitivity syndromes, spinal and bulbar muscular atrophy (Kennedy's disease).
The immune system function of RORC proteins most likely resides with expression of the RORγt isoform by immature CD4+/CD8+ cells in the thymus [34, 139] and in lymphoid tissue inducer (LTi) cells [35].
Clotrimazole [105] and T0901317 [67] although acting at other sites, function as antagonists of the constitutive androstane receptor.
Nomenclature
Hepatocyte nuclear factor‐4‐α
Hepatocyte nuclear factor‐4‐γ
Systematic nomenclature
NR2A1
NR2A2
HGNC, UniProt
HNF4A, P41235
HNF4G, Q14541
Endogenous agonists
linoleic acid [163]
–
Selective antagonists
BI6015 [70]
–
Comments
HNF4α has constitutive transactivation activity [163] and binds DNA as a homodimer [62].
–
Nomenclature
Retinoid X receptor‐α
Retinoid X receptor‐β
Retinoid X receptor‐γ
Systematic nomenclature
NR2B1
NR2B2
NR2B3
HGNC, UniProt
RXRA, P19793
RXRB, P28702
RXRG, P48443
Sub/family‐selective agonists
bexarotene [16, 20, 141]
bexarotene [16, 20, 141]
bexarotene [16, 20, 141]
Selective agonists
CD3254 [49]
–
–
Nomenclature
Testicular receptor 2
Testicular receptor 4
Systematic nomenclature
NR2C1
NR2C2
HGNC, UniProt
NR2C1, P13056
NR2C2, P49116
Endogenous agonists
–
retinol [169], tretinoin [169]
Comments
Forms a heterodimer with TR4; gene disruption appears without effect on testicular development or function [130].
Forms a heterodimer with TR2.
Nomenclature
TLX
PNR
Systematic nomenclature
NR2E1
NR2E3
HGNC, UniProt
NR2E1, Q9Y466
NR2E3, Q9Y5X4
Agonists
BMS493 [53], tretinoin [53]
–
Comments
Gene disruption is associated with abnormal brain development [74, 102].
–
Nomenclature
COUP‐TF1
COUP‐TF2
V‐erbA‐related gene
Systematic nomenclature
NR2F1
NR2F2
NR2F6
HGNC, UniProt
NR2F1, P10589
NR2F2, P24468
NR2F6, P10588
Comments
Gene disruption is perinatally lethal [118].
Gene disruption is embryonically lethal [115].
Gene disruption impairs CNS development [151].
Nomenclature
Estrogen‐related receptor‐α
Estrogen‐related receptor‐β
Estrogen‐related receptor‐γ
Systematic nomenclature
NR3B1
NR3B2
NR3B3
HGNC, UniProt
ESRRA, P11474
ESRRB, O95718
ESRRG, P62508
Comments
Activated by some dietary flavonoids [136]; activated by the synthetic agonist GSK4716 [172] and blocked by XCT790 [156].
May be activated by DY131 [162].
May be activated by DY131 [162].
Nomenclature
Nerve Growth factor IB
Nuclear receptor related 1
Neuron‐derived orphan receptor 1
Systematic nomenclature
NR4A1
NR4A2
NR4A3
HGNC, UniProt
NR4A1, P22736
NR4A2, P43354
NR4A3, Q92570
Comments
An endogenous agonist, cytosporone B, has been described [164], although structural analysis and molecular modelling has not identified a ligand binding site [4, 39, 150].
–
–
Nomenclature
Steroidogenic factor 1
Liver receptor homolog‐1
Systematic nomenclature
NR5A1
NR5A2
HGNC, UniProt
NR5A1, Q13285
NR5A2, O00482
Comments
Reported to be inhibited by AC45594 [30] and SID7969543 [88].
[3H]aldosterone (Selective Agonist) [44, 135] – Rat
[3H]ORG2058 (Selective Agonist)
Comments
Pre‐receptor ligand specificity is provided for the MR in tissues associated with maintenance of sodium homeostasis by the co‐expression of 11β‐hydroxysteroid dehydrogenase type II which converts cortisol (corticosterone in rodents) to their inactive forms. Given the increasing use of Danio rerio (zebrafish) as an experimental model, it is important to note that progesterone (and spironolactone) is a MR agonist in fish [42].
Authors: Lars Bärfacker; Alexander Kuhl; Alexander Hillisch; Rolf Grosser; Santiago Figueroa-Pérez; Heike Heckroth; Adam Nitsche; Jens-Kerim Ergüden; Heike Gielen-Haertwig; Karl-Heinz Schlemmer; Joachim Mittendorf; Holger Paulsen; Johannes Platzek; Peter Kolkhof Journal: ChemMedChem Date: 2012-07-12 Impact factor: 3.466
Authors: Marcos L Sznaidman; Curt D Haffner; Patrick R Maloney; Adam Fivush; Esther Chao; Donna Goreham; Michael L Sierra; Christelle LeGrumelec; H Eric Xu; Valerie G Montana; Millard H Lambert; Timothy M Willson; William R Oliver; Daniel D Sternbach Journal: Bioorg Med Chem Lett Date: 2003-05-05 Impact factor: 2.940