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. 2021 Sep 16;178(Suppl 1):S246–S263. doi: 10.1111/bph.15540

THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: Nuclear hormone receptors

Stephen P H Alexander 1, John A Cidlowski 2, Eamonn Kelly 3, Alistair Mathie 4, John A Peters 5, Emma L Veale 4, Jane F Armstrong 6, Elena Faccenda 6, Simon D Harding 6, Adam J Pawson 6, Christopher Southan 5, Jamie A Davies 6, Laurel Coons 7, Peter J Fuller 8, Kenneth S Korach 9, Morag J Young 10
PMCID: PMC9513947  PMID: 34529827

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.

Conflict of interest

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.

Family structure

S247 1A. Thyroid hormone receptors

S248 1B. Retinoic acid receptors

S249 1C. Peroxisome proliferator‐activated receptors

S250 1D. Rev‐Erb receptors

S251 1F. Retinoic acid‐related orphans

S252 1H. Liver X receptor‐like receptors

S253 1I. Vitamin D receptor‐like receptors

S254 2A. Hepatocyte nuclear factor‐4 receptors

S255 2B. Retinoid X receptors

S255 2C. Testicular receptors

S256 2E. Tailless‐like receptors

S256 2F. COUP‐TF‐like receptors

S257 3B. Estrogen‐related receptors

S257 4A. Nerve growth factor IB‐like receptors

S258 5A. Fushi tarazu F1‐like receptors

S259 6A. Germ cell nuclear factor receptors

S259 0B. DAX‐like receptors

S260 Steroid hormone receptors

S260 3A. Estrogen receptors

S261 3C. 3‐Ketosteroid receptors

1A. Thyroid hormone receptors

Overview

Thyroid hormone receptors (TRs, nomenclature as agreed by the NC‐IUPHAR Subcommittee on Nuclear Hormone Receptors [ 1 , 40 ]) 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 (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]

Nomenclature Thyroid hormone receptor‐α Thyroid hormone receptor‐β
Systematic nomenclature NR1A1 NR1A2
HGNC, UniProt THRA , P10827 THRB , P10828
Rank order of potency triiodothyronine > T4 triiodothyronine > T4
Agonists dextrothyroxine [19] dextrothyroxine [19]
Selective agonists – sobetirome [24, 128]
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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

Overview

Retinoic acid receptors (nomenclature as agreed by the NC‐IUPHAR Subcommittee on Nuclear Hormone Receptors [ 1 , 46 ]) 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]

Nomenclature Retinoic acid receptor‐α Retinoic acid receptor‐β Retinoic acid receptor‐γ
Systematic nomenclature NR1B1 NR1B2 NR1B3
HGNC, UniProt RARA , P10276 RARB , P10826 RARG , P13631
Agonists tretinoin [23] tretinoin [23] tretinoin [23]
Sub/family‐selective agonists tazarotene [23] tazarotene [23], adapalene [22] tazarotene [23], adapalene [22]
Selective agonists BMS753 [45], tamibarotene [146], Ro 40‐6055 [31] AC261066 [87], AC55649 [86, 87] AHPN [22]
Selective antagonists Ro 41‐5253 (pIC50 6.3–7.2) [2, 68] – MM 11253 [75]
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Comments

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

Overview

Peroxisome proliferator‐activated receptors (PPARs, nomenclature as agreed by the NC‐IUPHAR Subcommittee on Nuclear Hormone Receptors [ 1 , 99 ]) 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‐Δ12,14‐PGJ2 , prostacyclin (PGI2 ), many fatty acids and their oxidation products, lysophosphatidic acid (LPA) [96], 13‐HODE, 15S‐HETE, Paz‐PC, azelaoyl‐PAF and leukotriene B4 (LTB4 ). 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]

Nomenclature Peroxisome proliferator‐activated receptor‐α Peroxisome proliferator‐activated receptor‐β/δ Peroxisome proliferator‐activated receptor‐γ
Systematic nomenclature NR1C1 NR1C2 NR1C3
HGNC, UniProt PPARA , Q07869 PPARD , Q03181 PPARG , P37231
Selective agonists GW7647 [17, 18], CP‐775146 [66], pirinixic acid [155], gemfibrozil [29] GW0742X [51, 140], GW501516 [110] GW1929 [17], bardoxolone (Partial agonist) [149], rosiglitazone [58, 79, 161], troglitazone [58, 161], pioglitazone [58, 125, 161], ciglitazone [58]
Selective antagonists GW6471 (pIC50 6.6) [158] GSK0660 (pIC50 6.5) [129] T0070907 (pKi 9) [76], GW9662 (Irreversible inhibition) (pIC50 8.1) [77], CDDO‐Me (pKi 6.9) [149]
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Comments

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

Overview

Rev‐erb receptors (nomenclature as agreed by the NC‐IUPHAR Subcommittee on Nuclear Hormone Receptors [ 1 , 7 ]) 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]

Nomenclature Rev‐Erb‐α Rev‐Erb‐β
Systematic nomenclature NR1D1 NR1D2
HGNC, UniProt NR1D1 , P20393 NR1D2 , Q14995
Endogenous agonists heme [119, 160] heme [95, 119, 160]
Selective agonists GSK4112 [52], GSK4112 [71] –
Selective antagonists SR8278 (pIC50 6.5) [71] –
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1F. Retinoic acid‐related orphans

Overview

Retinoic acid receptor‐related orphan receptors (ROR, nomenclature as agreed by the NC‐IUPHAR Subcommittee on Nuclear Hormone Receptors [ 1 , 7 ]) 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]

Nomenclature RAR‐related orphan receptor‐α RAR‐related orphan receptor‐β RAR‐related orphan receptor‐γ
Systematic nomenclature NR1F1 NR1F2 NR1F3
HGNC, UniProt RORA , P35398 RORB , Q92753 RORC , P51449
Endogenous agonists cholesterol [65, 112] – –
Selective agonists 7‐hydroxycholesterol [14], cholesterol sulphate [14, 65] – –
Comments – – 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].
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Comments

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

Overview

Liver X and farnesoid X receptors (LXR and FXR, nomenclature as agreed by the NC‐IUPHAR Subcommittee on Nuclear Hormone Receptors [ 1 , 103 ]) 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]

Nomenclature Farnesoid X receptor Farnesoid X receptor‐β Liver X receptor‐α Liver X receptor‐β
Systematic nomenclature NR1H4 NR1H5 NR1H3 NR1H2
HGNC, UniProt NR1H4 , Q96RI1 NR1H5P , – NR1H3 , Q13133 NR1H2 , P55055
Potency order chenodeoxycholic acid > lithocholic acid, deoxycholic acid [90, 113] – 20S‐hydroxycholesterol, 22R‐hydroxycholesterol, 24(S)‐hydroxycholesterol > 25‐hydroxycholesterol, 27‐hydroxycholesterol [78] 20S‐hydroxycholesterol, 22R‐hydroxycholesterol, 24(S)‐hydroxycholesterol > 25‐hydroxycholesterol, 27‐hydroxycholesterol [78]
Endogenous agonists – lanosterol [111] – Mouse – –
Selective agonists GW4064 [92], obeticholic acid [114], fexaramine [33] – – –
Selective antagonists guggulsterone (pIC50 5.7–6) [157] – – –
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Comments

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

Overview

Vitamin D (VDR), Pregnane X (PXR) and Constitutive Androstane (CAR) receptors (nomenclature as agreed by the NC‐IUPHAR Subcommittee on Nuclear Hormone Receptors [ 1 , 103 ]) 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]

Nomenclature Vitamin D receptor Pregnane X receptor Constitutive androstane receptor
Systematic nomenclature NR1I1 NR1I2 NR1I3
HGNC, UniProt VDR , P11473 NR1I2 , O75469 NR1I3 , Q14994
Endogenous agonists 1,25‐dihydroxyvitamin D3 [11, 38] 17β‐estradiol [63] –
Selective agonists seocalcitol [26, 153], doxercalciferol hyperforin [104, 152], 5β‐pregnane‐3,20‐dione [63], lovastatin [80], rifampicin [15, 80] TCPOBOP [144] – Mouse, CITCO [89]
Selective antagonists TEI‐9647 (pIC50 8.2) [124] – Chicken, ZK159222 (pIC50 7.5) [41, 59] – –
Comments – – Clotrimazole [105] and T0901317 [67] although acting at other sites, function as antagonists of the constitutive androstane receptor.
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2A. Hepatocyte nuclear factor‐4 receptors

Overview

The nomenclature of hepatocyte nuclear factor‐4 receptors is agreed by the NC‐IUPHAR Subcommittee on Nuclear Hormone Receptors [ 1 , 7 ]. 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]

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]. –
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2B. Retinoid X receptors

Overview

Retinoid X receptors (nomenclature as agreed by the NC‐IUPHAR Subcommittee on Nuclear Hormone Receptors [ 1 , 47 ]) 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]

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] – –
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2C. Testicular receptors

Overview

Testicular receptors (nomenclature as agreed by the NC‐IUPHAR Subcommittee on Nuclear Hormone Receptors [ 7 ]) 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]

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.
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2E. Tailless‐like receptors

Overview

Tailless‐like receptors (nomenclature as agreed by the NC‐IUPHAR Subcommittee on Nuclear Hormone Receptors [ 7 ]) 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]

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]. –
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2F. COUP‐TF‐like receptors

Overview

COUP‐TF‐like receptors (nomenclature as agreed by the NC‐IUPHAR Subcommittee on Nuclear Hormone Receptors [ 1 , 7 ]) 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]

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].
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3B. Estrogen‐related receptors

Overview

Estrogen‐related receptors (nomenclature as agreed by the NC‐IUPHAR Subcommittee on Nuclear Hormone Receptors [ 7 ]) 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]

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].
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4A. Nerve growth factor IB‐like receptors

Overview

Nerve growth factor IB‐like receptors (nomenclature as agreed by the NC‐IUPHAR Subcommittee on Nuclear Hormone Receptors [ 7 ]) 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]

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]. – –
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5A. Fushi tarazu F1‐like receptors

Overview

Fushi tarazu F1‐like receptors (nomenclature as agreed by the NC‐IUPHAR Subcommittee on Nuclear Hormone Receptors [ 7 ]) 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]

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]. –
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6A. Germ cell nuclear factor receptors

Overview

Germ cell nuclear factor receptors (nomenclature as agreed by the NC‐IUPHAR Subcommittee on Nuclear Hormone Receptors [ 7 ]) 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]

Nomenclature Germ cell nuclear factor
Systematic nomenclature NR6A1
HGNC, UniProt NR6A1 , Q15406
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0B. DAX‐like receptors

Overview

Dax‐like receptors (nomenclature as agreed by the NC‐IUPHAR Subcommittee on Nuclear Hormone Receptors [ 7 ]) 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]

Nomenclature DAX1 SHP
Systematic nomenclature NR0B1 NR0B2
HGNC, UniProt NR0B1 , P51843 NR0B2 , Q15466
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Steroid hormone receptors

Overview

Steroid hormone receptors (nomenclature as agreed by the NC‐IUPHAR Subcommittee on Nuclear Hormone Receptors [ 1 , 28 , 85 ]) 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( HSP90AB1 , P08238) and immunophilin FKBP52: FKBP4 , 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 ( GPER1 , Q99527, also known as GPR30, see [116]) has been described. Human orthologues of 7TM 'membrane progestin receptors' ( PAQR7 , PAQR8 and PAQR5 ), 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

Overview

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]

Nomenclature Estrogen receptor‐α Estrogen receptor‐β
Systematic nomenclature NR3A1 NR3A2
HGNC, UniProt ESR1 , P03372 ESR2 , Q92731
Endogenous agonists estriol [73], estrone [73] –
Selective agonists propylpyrazoletriol [72, 133], ethinylestradiol [61] WAY200070 [91], diarylpropionitrile [98, 133], prinaberel [27, 91]
Sub/family‐selective antagonists bazedoxifene (pIC50 7.6) [101] bazedoxifene (pIC50 7.1) [101]
Selective antagonists clomiphene (pKi 8.9) [3], methyl‐piperidino‐pyrazole (pKi 8.6) [137] R,R‐THC (pKi 8.4) [97, 138], PHTPP (pKi 6.9) [168]
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Comments

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 [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 [109].

3C. 3‐Ketosteroid receptors

Overview

Steroid hormone receptors (nomenclature as agreed by the NC‐IUPHAR Subcommittee on Nuclear Hormone Receptors [ 1 , 28 , 85 ]) 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]

Nomenclature Androgen receptor Glucocorticoid receptor
Systematic nomenclature NR3C4 NR3C1
HGNC, UniProt AR , P10275 NR3C1 , P04150
Rank order of potency dihydrotestosterone > testosterone cortisol, corticosterone≫aldosterone, deoxycortisone [123]
Endogenous agonists dihydrotestosterone [142] –
Selective agonists testosterone propionate [93], mibolerone [50], fluoxymesterone [60], methyltrienolone [148], dromostanolone propionate fluticasone propionate [10], flunisolide [3], beclometasone [3], methylprednisolone [3], betamethasone [3], budesonide [100]
Selective antagonists bicalutamide (pKi 7.7) [69], PF0998425 (pIC50 7.1–7.5) [84], enzalutamide (pIC50 7.4) [143], nilutamide (pIC50 7.1–7.1) [131], hydroxyflutamide (pEC50 6.6) [148], galeterone (pIC50 6.4) [56], flutamide (Displacement of 3[H] testosterone from wild‐type androgen receptors) (pKi 5.4) [147] onapristone (pIC50 7.6) [165], ZK112993
Labelled ligands [3H]dihydrotestosterone (Selective Agonist), [3H]methyltrienolone (Selective Agonist), [3H]mibolerone (Agonist) [3H]dexamethasone (Agonist)
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Nomenclature Mineralocorticoid receptor Progesterone receptor
Systematic nomenclature NR3C2 NR3C3
HGNC, UniProt NR3C2 , P08235 PGR , P06401
Rank order of potency corticosterone, cortisol, aldosterone, progesterone [123] progesterone
Endogenous agonists deoxycorticosterone [123], aldosterone [57, 123], cortisol [57, 123], corticosterone progesterone [37]
Selective agonists – medroxyprogesterone (Affinity at human PR‐A) [166], ORG2058, levonorgestrel [9, 126]
Selective antagonists finerenone (pIC50 7.7) [5], eplerenone (pKi 6.9) [6], onapristone (pIC50 6.3) [165], RU28318, ZK112993 ulipristal acetate (pIC50 9.7) [121], mifepristone (Mixed) (pKi 9) [167], onapristone (pKi 7.7) [55], ZK112993
Labelled ligands [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]. –
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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 [43, 81]. Mutations in AR underlie testicular feminization and androgen insensitivity syndromes, spinal and bulbar muscular atrophy (Kennedy's disease).

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