The Concise Guide to Pharmacology 2013/14: Nuclear Hormone Receptors

The Concise Guide to PHARMACOLOGY 2013/14 provides concise overviews of the key properties of over 2000 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.12444/full. Nuclear hormone receptors are one of the seven major pharmacological targets into which the Guide is divided, with the others being G protein-coupled receptors, ligand-gated ion channels, ion channels, catalytic receptors, transporters and enzymes. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. A new landscape format has easy to use tables comparing related targets. It is a condensed version of material contemporary to late 2013, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in previous Guides to Receptors and Channels. It is produced in conjunction with NC-IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR-DB and the Guide to Receptors and Channels, providing a permanent, citable, point-in-time record that will survive database updates.


An Introduction to Nuclear Hormone Receptors
Nuclear hormone receptors are specialised transcription factors with commonalities of sequence and structure, which bind as homo-or heterodimers to specific consensus sequences of DNA (response elements) in the promoter region of particular target genes. They regulate (either promoting or repressing) transcription of these target genes in response to a variety of endogenous ligands. Endogenous agonists are hydrophobic entities which, when bound to the receptor promote conformational changes in the receptor to allow recruitment (or dissociation) of protein partners, generating a large multiprotein complex.
Two major subclasses of nuclear hormone receptors with identified endogenous agonists can be identified: steroid and nonsteroid 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. Nonsteroid hormone receptors typically exhibit a greater distribution in the nucleus in the unliganded state and interact with other nuclear hormone receptors to form heterodimers, as well as with other regulators of gene transcription, leading to changes in gene transcription upon agonist binding.
Selectivity of gene regulation is brought about through interaction of nuclear hormone receptors with particular consensus sequences of DNA, which are arranged typically as repeats or inverted palindromes to allow accumulation of multiple transcription factors in the promoter regions of genes.

1A. Thyroid Hormone Receptors
Overview: Thyroid hormone receptors (TRs, nomenclature as agreed by NC-IUPHAR Committee on Nuclear Receptors, [3]) are nuclear hormone receptors of the NR1A family, with diverse roles regulating macronutrient metabolism, cognition and cardiovascular homeostasis. TRs are activated by thyroxine (T4) and thyroid hormone (T3). Once activated by a ligand, the receptor acts as a transcription factor either as a monomer, homodimer or heterodimer with members of the retinoid X receptor family. NH-3 has been described as an antagonist at TRs with modest selectivity for TRβ [4].

Nomenclature
Thyroid hormone receptor-α Thyroid hormone receptor-β Comments: An interaction with integrin αVβ3 has been suggested to underlie plasma membrane localization of TRs and non-genomic signalling [1]. One splice variant, TRα2, lacks a functional DNA-binding domain and appears to act as a transcription suppressor.
Although radioligand binding assays have been described for these receptors, the radioligands are not commercially available.

1B. Retinoic acid receptors
Overview: Retinoic acid receptors (nomenclature as agreed by NC-IUPHAR Committee on Nuclear Receptors, [8]) are nuclear hormone receptors of the NR1B family activated by the vitamin A-derived agonists all-trans-retinoic acid (ATRA) and 9-cis-retinoic acid, and the RAR-selective synthetic agonists TTNPB and adapalene. Comments: Ro 41-5253 has been suggested to be a PPARγ agonist [17]. LE135 is an antagonist with selectivity for RARα and RARβ compared with RARγ [14]. [9] is a family-selective antagonist.

1C. Peroxisome proliferator-activated receptors
Overview: Peroxisome proliferator-activated receptors (PPARs, nomenclature as agreed by NC-IUPHAR Committee on Nuclear Receptors, [33]) are nuclear hormone receptors of the NR1C family, with diverse roles regulating lipid homeostasis, cellular differentiation, proliferation and the immune response. PPARs have many potential endogenous agonists [21,33], including 15-deoxy-Δ 12,14 -PGJ2, prostacyclin (PGI2), many fatty acids and their oxidation products, lysophosphatidic acid (LPA) [32], 13-HODE, 15S-HETE, Paz-PC, azelaoyl-PAF and leukotriene B4 (LTB4). bezafibrate acts as a non-selective agonist for the PPAR family [41]. These receptors also bind hypolipidaemic drugs (PPARα) and anti-diabetic thiazolidinediones (PPARγ), as well as many non-steroidal anti-inflammatory drugs, such as sulindac and indomethacin. Once activated by a ligand, the receptor forms a heterodimer with members of the retinoid X receptor family and can act as a transcription factor. Although radioligand binding assays have been described for all three receptors, the radioligands are not commercially available. Commonly, receptor occupancy studies are conducted using fluorescent ligands and truncated forms of the receptor limited to the ligand binding domain.

1D. Rev-Erb receptors
Overview: Rev-erb receptors (nomenclature as agreed by NC-IUPHAR committee on nuclear hormone receptors [45]) have yet to be officially paired with an endogenous ligand, but are thought to be activated by heme.

1F. Retinoic acid-related orphans
Overview: Retinoic acid receptor-related orphan receptors (ROR, nomenclature as agreed by NC-IUPHAR Committee on Nuclear Receptors, [50]) have yet to be assigned a definitive endogenous ligand, although RORα may be synthesized with a 'captured' agonist such as cholesterol [52][53].

1H. Liver X receptor-like receptors
Overview: Liver X and farnesoid X receptors (LXR and FXR, nomenclature as agreed by NC-IUPHAR Committee on Nuclear Receptors, [62]) are members of a steroid analogue-activated nuclear receptor subfamily (ENSFM00500000269785), which form heterodimers with members of the retinoid X receptor family. Endogenous ligands for LXRs include hydroxycholesterols (OHC), while FXRs appear to be activated by bile acids.

2A. Hepatocyte nuclear factor-4 receptors
Overview: Hepatocyte nuclear factor-4 receptors (nomenclature as agreed by NC-IUPHAR committee on nuclear hormone receptors [85]) have yet to be officially paired with an endogenous ligand, although linoleic acid has been described to activate HNF4α receptors.

2C. Testicular receptors
Overview: Testicular receptors (nomenclature as agreed by NC-IUPHAR committee on nuclear hormone receptors [94]) have yet to be officially paired with an endogenous ligand, although testicular receptor 4 has been reported to respond to retinoids.

2E. Tailless-like receptors
Overview: Tailless-like receptors (nomenclature as agreed by NC-IUPHAR committee on nuclear hormone receptors [97]) have yet to be officially paired with an endogenous ligand.

2F. COUP-TF-like receptors
Overview: COUP-TF-like receptors (nomenclature as agreed by NC-IUPHAR committee on nuclear hormone receptors [100]) have yet to be officially paired with an endogenous ligand.

4A. Nerve growth factor IB-like receptors
Overview: Nerve growth factor IB-like receptors (nomenclature as agreed by NC-IUPHAR committee on nuclear hormone receptors [110]) have yet to be officially paired with an endogenous ligand.

5A. Fushi tarazu F1-like receptors
Overview: Fushi tarazu F1-like receptors (nomenclature as agreed by NC-IUPHAR committee on nuclear hormone receptors [114]) have yet to be officially paired with an endogenous ligand.

Steroid hormone receptors
Overview: Steroid hormone receptors (nomenclature as agreed by NC-IUPHAR Committee on Nuclear Receptors, [120,132]) are nuclear hormone receptors of the NR3 class, with endogenous agonists that may be divided into 3-hydroxysteroids (estrone and 17β-estradiol) and 3-ketosteroids (dihydrotestosterone [DHT], aldosterone, cortisol, corticosterone, progesterone and testosterone). These receptors exist as dimers coupled with chaperone molecules (such as hsp90 (HSP90AB1, P08238) and immunophilin FKBP52:FKBP4, Q02790), which are shed on binding the steroid hormone. Although rapid signalling phenomena are observed [130,138], the principal signalling cascade appears to involve binding of the activated receptors to nuclear hormone response elements of the genome, with a 15-nucleotide consensus sequence AGAACAnnnTGTTCT (i.e. an inverted palindrome) as homo-or heterodimers. They also affect transcription by protein-protein interactions with other transcription factors, such as activator protein 1 (AP-1) and nuclear factor κB (NF-κB). Splice variants of each of these receptors can form functional or non-functional monomers that can dimerize to form functional or non-functional receptors. For example, alternative splicing of PR mRNA produces A and B monomers that combine to produce functional AA, AB and BB receptors with distinct characteristics [148].
A 7TM receptor responsive to estrogen (GPER1, Q99527, also known as GPR30, see [137]) has been described. Human orthologues of 7TM 'membrane progestin receptors' (PAQR7, PAQR8 and PAQR5), initially discovered in fish [151][152], appear to localize to intracellular membranes and respond to 'non-genomic' progesterone analogues independently of G proteins [142]. Comments: R,R-THC exhibits partial agonist activity at ERα [134,146]. Estrogen receptors may be blocked non-selectively by tamoxifen and raloxifene and labelled by [ 3 H]17β-estradiol and [ 3 H]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 modula-tor) or SnuRM (selective nuclear receptor modulator). Y134 has been suggested to be an ERα-selective estrogen receptor modulator [136].