THE CONCISE GUIDE TO PHARMACOLOGY 2017/18: Nuclear hormone receptors

The Concise Guide to PHARMACOLOGY 2017/18 provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), 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. Although the Concise Guide represents approximately 400 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/10.1111/bph.13880/full. Nuclear hormone receptors are one of the eight major pharmacological targets into which the Guide is divided, with the others being: G protein‐coupled receptors, ligand‐gated ion channels, voltage‐gated ion channels, other ion channels, 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‐2017, and supersedes data presented in the 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature Committee of the Union of Basic and Clinical Pharmacology (NC‐IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate. © 2015 The British Pharmacological Society

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. Nonsteroid 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.

1A. Thyroid hormone receptors
Nuclear hormone receptors → 1A. Thyroid hormone receptors Overview: Thyroid hormone receptors (TRs, nomenclature as agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [41]) are nuclear hormone receptors of the NR1A family, with diverse roles regulating macronutrient metabolism, cognition and cardiovascular homeostasis. TRs are activated by thyroxine (T 4 ) and thyroid hormone (triiodothyronine). Once activated by a ligand, the receptor acts as a transcription factor either as a monomer, homodimer or het-erodimer with members of the retinoid X receptor family. NH-3 has been described as an antagonist at TRs with modest selectivity for TRβ [110]. Agonists dextrothyroxine [19] dextrothyroxine [19] Selective agonists -sobetirome [26,130] Comments: An interaction with integrin αVβ3 has been suggested to underlie plasma membrane localization of TRs and non-genomic signalling [8].One splice variant, TRα 2 , lacks a functional DNAbinding 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
Nuclear hormone receptors → 1B. Retinoic acid receptors Overview: Retinoic acid receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [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 [47].

1D. Rev-Erb receptors
Nuclear hormone receptors → 1D. Rev-Erb receptors Overview: Rev-erb receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [6]) have yet to be officially paired with an endogenous ligand, but are thought to be activated by heme.

1F. Retinoic acid-related orphans
Nuclear hormone receptors → 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 [6]) have yet to be assigned a definitive endogenous ligand, although RORα may be synthesized with a 'captured' agonist such as cholesterol [65,66].

1H. Liver X receptor-like receptors
Nuclear hormone receptors → 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 [105]) 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.

1I. Vitamin D receptor-like receptors
Nuclear hormone receptors → 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 [105]) 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 [105].

Nomenclature
Vitamin

2A. Hepatocyte nuclear factor-4 receptors
Nuclear hormone receptors → 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 [6]. 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.

2B. Retinoid X receptors
Nuclear hormone receptors → 2B. Retinoid X receptors Overview: Retinoid X receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [45]) are NR2B family members activated by alitretinoin and the RXR-selective agonists bexarotene and LG100268, sometimes referred to as rexinoids. UVI3003 [108] and HX 531 [37] have been described as a pan-RXR antagonists. These receptors form RXR-RAR heterodimers and RXR-RXR homodimers [22,96]. Comments Forms a heterodimer with TR4; gene disruption appears without effect on testicular development or function [132]. Forms a heterodimer with TR2.

2E. Tailless-like receptors
Nuclear hormone receptors → 2E. Tailless-like receptors Overview: Tailless-like receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [6]) have yet to be officially paired with an endogenous ligand.

Nuclear hormone receptors → 2F. COUP-TF-like receptors
Overview: COUP-TF-like receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [6]) have yet to be officially paired with an endogenous ligand.

Nuclear hormone receptors → 3B. Estrogen-related receptors
Overview: Estrogen-related receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [6]) have yet to be officially paired with an endogenous ligand.

4A. Nerve growth factor IB-like receptors
Nuclear hormone receptors → 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 [6]) have yet to be officially paired with an endogenous ligand.

6A. Germ cell nuclear factor receptors
Nuclear hormone receptors → 6A. Germ cell nuclear factor receptors Overview: Germ cell nuclear factor receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [6]) have yet to be officially paired with an endogenous ligand.

Nomenclature
Germ cell nuclear factor

0B. DAX-like receptors
Nuclear hormone receptors → 0B. DAX-like receptors Overview: Dax-like receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [6]) have yet to be officially paired with an endogenous ligand.