NUCLEAR RECEPTORS

Abstract

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. Germain P, Staels B, Dacquet C, Spedding M, Laudet V (2006). Overview of nomenclature of nuclear receptors. Pharmacol Rev58: 685–704. In man, 48 nuclear receptors have been identified from sequence analysis of the genome (see Benoit et al., 2006; Germain et al., 2006), only half of which have been ‘assigned’ a ligand by Nomenclature Committees of NC-IUPHAR. 19 families of nuclear receptors have been identified, allowing a systematic nomenclature of the format NRXYZ, where NR represents nuclear receptor, X the subfamily (1, 2, 3, 4, 5, 6 or 0), Y the group (A, B, C, D, F, H or I) and Z the individual member. Listed below are a number of putative nuclear receptors identified by NC-IUPHAR, for which only preliminary evidence for an endogenous ligand has been published. Abbreviations: AC45594, 4-heptoxyphenol; DY131, N-(4-(diethylaminobenzylidenyl)-N′-(4-hydroxybenzoyl)-hydrazine; GSK4112, 1,1-dimethylethyl-N-[(4-chlorophenyl)methyl]-N-[(5-nitro-2-thienyl)methyl])glycinate, also known as SR6452; GSK4716, 4-hydroxy-2-[(1E)-[4-(1-methylethyl)phenyl]methylene]hydrazide; SID7969543, ethyl 2-[2-[2-(2,3-dihydro-1,4-benzodioxin-7-ylamino)-2-oxoethyl]-1-oxoisoquinolin-5-yl]oxypropanoate; XCT790, (E)-3-[4-[[2,4-bis(trifluoromethyl)phenyl]methoxy]-3-methoxyphenyl]-2-cyano-N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]prop-2-enamide Benoit G, Cooney A, Giguere V, Ingraham H, Lazar M, Muscat G et al. (2006). International Union of Pharmacology. LXVI. Orphan nuclear receptors. Pharmacol Rev58: 798–836. Chanda D, Park JH, Choi HS (2008). Molecular basis of endocrine regulation by orphan nuclear receptor Small Heterodimer Partner. Endocr J55: 253–268. Deblois G, Giguere V (2011). 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Overview: Peroxisome proliferator-activated receptors (PPARs, nomenclature as agreed by NC-IUPHAR Committee on Nuclear Receptors, see Michalik et al., 2006) 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 (see Michalik et al., 2006), including 15-deoxy-Δ12,14-prostaglandin J2, prostacyclin, many fatty acids and their oxidation products, lysophosphatidic acid (McIntyre et al., 2003), 13-HODE, 15-HETE, Paz-PC, azelaoyl-PAF, and leukotriene B4. 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. As with the estrogen receptor antagonists, many agents show tissue-selective efficacy (e.g. Bishop-Bailey, 2000; Rocchi et al., 2001; Nakamuta et al., 2002). Agonists with mixed activity at PPARα and PPARγ have also been described (e.g. Doebber et al., 2004; Guo et al., 2004; Xu et al., 2004). Abbreviations: 13-HODE, 13-hydroxyoctadecadienoic acid; 15-HETE, 15-hydroxyeicosatetraenoic acid; azelaoyl-PAF, 1-O-hexadecyl-2-O-(9-carboxyoctanoyl)-sn-glyceryl-3-phosphocholine; BADGE, bisphenol A diglycidyl ether; CDDO, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid; CDDO-Me, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid methyl ester; GSK0660, ; GW1929, (2S)-([2-benzoylphenyl]amino)-3-(4-[2-{methylpyridin-2-ylamino}ethoxy]phenyl)propionic acid; GW501516, 2-methyl-4([{(4-methyl-2-[4-trifluoromethylphenyl]-1,3-thiazol-5-yl)methyl}sulfanyl]phenoxy)acetic acid, GW7647, 2-([4-{2-([{cyclohexylamino}carbonyl][4-cyclohexylbutyl]amino)ethyl}phenyl]thio)-2-methylpropanoic acid; GW9662, 2-chloro-5-nitro-N-phenylbenzamide; L165041, (4-[3-{4-acetyl-3-hydroxy-2-propylphenoxy}propoxyl]phenoxy)acetic acid; Paz-PC, 1-palmitoyl-2-azelaoyl-sn-glycero-3-phosphocholine; T0070907, 2-chloro-5-nitro-N-(4-pyridyl)benzamide; WY14643, N-(3-[2-quinolinylmethoxy]phenyl)-trifluoromethanesulphonamide Belvisi MG, Mitchell JA (2009). 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Overview: Cytoplasmic cellular retinoid binding proteins I (ENSG00000114115), II (ENSG00000114113), III (ENSG00000139194) and IV (ENSG00000162444) are thought to control the levels of intracellular retinoids available for interaction with their receptors (Li, 1999). [3H]-ATRA and [3H]-9-cis-retinoic acid have been used to label RARs and RXRs, respectively. Retinoic acid receptors (nomenclature as agreed by NC-IUPHAR Committee on Nuclear Receptors, see Germain et al., 2006a) 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. Ro415253 has been suggested to be a PPARγ agonist (Schupp et al., 2007). LE135 is an antagonist with selectivity for RARα and RARβ compared to RARγ (Li et al., 1999). Retinoid X receptors (nomenclature as agreed by NC-IUPHAR Committee on Nuclear Receptors, see Germain et al., 2006b) are NR2B family members activated by 9-cis-retinoic acid and the RXR-selective agonists LGD1069 and LG100268, sometimes referred to as rexinoids. These receptors form RXR–RAR heterodimers and RXR–RXR homodimers (Mangelsdorf and Evans, 1995; Chambon, 1996). UVI3003 has been described as a pan-RXR antagonist (Nahoum et al., 2007). Retinoic acid-related orphan receptors (ROR, nomenclature as agreed by NC-IUPHAR Committee on Nuclear Receptors, see Benoit et al., 2006) have yet to be assigned a definitive endogenous ligand, although RORα may be synthesised with a ‘captured’ agonist such as cholesterol (Kallen et al., 2002; 2004). ATRA shows selectivity for RORβ within the ROR family (Stehlin-Gaon et al., 2003). RORα has been suggested to be a nuclear receptor responding to melatonin (Wiesenberg et al., 1995). Abbreviations: 7-OHC, 7-hydroxycholesterol; AC261066, 4-(4-[2-butoxyethoxy]-5-methyl-2-thiazolyl)-2-fluorobenzoic acid; AC55649, 4′-octyl-[1,1′-biphenyl]-4-carboxylic acid; AHPN, 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid, also known as CD437; ATRA, all-trans-retinoic acid; CD1530, 4-(6-hydroxy-7-tricyclo[3.3.1.13,7]dec-1-yl-2-naphthalenyl)benzoic acid; CD3254, (E)-3-[4-hydroxy-3-(3,5,5,8,8-pentamethyl-6, 7-dihydronaphthalen-2-yl)phenyl]prop-2-enoic acid; LE135, 4-(7,8,9,10-tetrahydro-5,7,7,10,10-pentamethyl-5H-benzo[e]naphtho[2,3-b][1,4]diazepin-13-yl)benzoic acid; LG100268, 6-(1-[3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl]cyclopropyl) nicotinic acid; LGD1069, 4-(1-[3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl]ethenyl) benzoic acid; MM11253, 6-(2-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl]-1,3-dithiolan-2-yl)-2-naphthalenecarboxylic acid; Ro406055, 4-([5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl]carboxamido)benzoic acid (also known as AM580); Ro415253, 4-[2-(7-heptoxy-4,4-dimethyl-1,1-dioxo-2,3-dihydrothiochromen-6-yl)prop-1-enyl]benzoic acid, also known as LG629; TTNPB, (E)-4-(2-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl]-1-propenyl)benzoic acid; UVI3003, 3-(4-hydroxy-3-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-{pentyloxy}-2-naphthalenyl]phenyl)-2-propenoic acid Benoit G, Cooney A, Giguere V, Ingraham H, Lazar M, Muscat G et al. 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These receptors exist as dimers coupled with chaperone molecules (such as HSP90 [ENSG00000166598] and immunophilin FKBP52 [ENSG00000004478]), which are shed on binding the steroid hormone. Although rapid signalling phenomena are observed (see Levin, 2008; Prossnitz and Maggiolini, 2009), 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 nonfunctional 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 (Vegeto et al., 1993). A 7TM receptor responsive to estrogen (GPE, also known as GPR30, ENSG00000164850, see Prossnitz et al., 2008) has been described. Human orthologues of 7TM ‘membrane progestin receptors’ (ENSG00000182749, ENSG00000170915 and ENSG00000137819), initially discovered in fish (Zhu et al., 2003a; 2003b), appear to localize to intracellular membranes and appear to respond to ‘non-genomic’ progesterone analogues independently of G proteins (Smith et al., 2008). [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 (Gass et al., 1998; Leonhardt et al., 1998). Mutations in AR underlie testicular feminization and androgen insensibility syndromes, spinal and bulbar muscular atrophy (Kennedy's disease). r,r-THC exhibits partial agonist activity at ERα (Meyers et al., 1999; Sun et al., 1999). Estrogen receptors may be blocked non-selectively by tamoxifen and raloxifene, and labelled by [3H]-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 (Ning et al., 2007). Additional ‘orphan’ estrogen-receptor-related proteins have been described (ERRα ENSG00000173153; ERRβ ENSG00000119715; ERRγ ENSG00000057103); DY131 is an agonist with selectivity for ERRβ and ERRγ compared to ERRα, ERα and ERβ (Yu and Forman, 2005). Abbreviations: DHT, 5α-dihydrotestosterone; DPN, 2,3-bis(4-hydroxyphenyl)propionitrile; DY131, N′-([1E]-[4-(diethylamino)phenyl]methylene)-4-hydroxybenzohydrazide; MPP, 1,3-bis(4-hydroxyphenyl)-4-methyl-5-(4-[2-piperidinylethoxy]phenol)-1H-pyrazole; ORG2058, 16-α-ethyl-21-hydroxy-19-norpregn-4-ene-3,20-dione; PPT, 4,4′,4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol; PHTPP, 4-(2-phenyl-5,7-bis[trifluoromethyl]pyrazolo[1,5-a]pyrimidin-3-yl)phenol ; R1881, 17β-hydroxy-17α-methyl-estra-4,9,11-triene-3-one, also known as methyltrienolone; r,r-THC, r,r-tetrahydrochrysene; RU26988, 11β,17β-dihydroxy-21-methyl-17α-pregna-1,4,6-trien-20-yl-3-on; RU28318, 3-oxo-7-propyl-17-hydroxy-androstan-4-en-17-yl; RU28362, 11β,17β-dihydroxy-6-methyl-17-(1-propionyl)androsta-1,4,6-triene-3-one; Y134, (6-hydroxy-2-[4-hydroxyphenyl]-benzo[b]thiophen-3-yl)-(4-[4-isopropylpiperazin-1-yl]-phenyl)methanone; WAY200070, 7-bromo-2-(4-hydroxyphenyl)-1,3-benzoxazol-5-ol; ZK112993, 11β-(4-acetylphenyl)-17β-hydroxyl-17α-(1-propinyl)-4,8-estradiene-3-one Blaustein JD (2008). 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Overview: Thyroid hormone receptors (TRs, nomenclature as agreed by NC-IUPHAR Committee on Nuclear Receptors, see Flamant et al., 2006) 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. An interaction with integrin αVβ3 has been suggested to underlie plasma membrane localization of thyroid hormone receptors and non-genomic signalling (Bergh et al., 2005). 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. 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Abbreviations: CITCO, 6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde-O-(3,4-dichlorobenzyl)oxime; EB1089, (1R,3S,5Z)-5-[(2E)-2-[(1R,3aS,7aR)-1-[(1R,2E,4E)-6-ethyl-6-hydroxy-1-methyl-2,4-octadien-1-yl]-octahydro-7α-methyl-4H-inden-4-ylidene]ethylidene]-4-methylene-1,3-cyclohexanediol, also known as seocalcitol; TEI9647, (23s)-25-dehydro-1α hydroxyvitamin D3-26,23-lactone; TCPOBOP, 1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene; ZK159222, butyl 1-[(E,1R,4R)-4-[(1R,3aS,4E,7aR)-4-[(2Z)-2-[(3S,5R)-3,5-dihydroxy-2-methylidenecyclohexylidene]ethylidene]-7a-methyl-2,3,3a,5,6,7-hexahydro-1H-inden-1-yl]-1-hydroxypent-2-enyl]cyclopropane-1-carboxylate Bikle D (2009). Nonclassic actions of vitamin D. J Clin Endocrinol Metab94: 26–34. Bikle DD (2011). Vitamin D: an ancient hormone. Exp Dermatol20: 7–13. Bouillon R, Carmeliet G, Verlinden L et al. (2008). Vitamin D and human health: lessons from vitamin D receptor null mice. Endocr Rev29: 726–776. 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