THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Nuclear hormone receptors

The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 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 (http://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.14750. 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‐2019, and supersedes data presented in the 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC‐IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

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

1C. Peroxisome proliferator-activated receptors
Nuclear hormone receptors → 1C. Peroxisome proliferator-activated receptors Overview: Peroxisome proliferator-activated receptors (PPARs, nomenclature as agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [96]) 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 [11,96], including 15-deoxy-12,14 -PGJ 2 , prostacyclin (PGI 2 ), many fatty acids and their oxidation products, lysophosphatidic acid (LPA) [93], 13-HODE, 15S-HETE, Paz-PC, azelaoyl-PAF and leukotriene B4 (LTB 4 ). Bezafibrate acts as a non-selective agonist for the PPAR family [152]. These receptors also bind hypolipidaemic drugs (PPARα) and anti-diabetic thiazolidinediones (PPARγ), as well as many non-steroidal antiinflammatory 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
Nuclear hormone receptors → 1D. Rev-Erb receptors Overview: Rev-erb receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [5]) 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 [5]) have yet to be assigned a definitive endogenous ligand, although RORα may be synthesized with a 'captured' agonist such as cholesterol [61,62].

Nomenclature
RAR-related orphan receptor-α RAR-related orphan receptor-β RAR-related orphan receptor-γ The immune system function of RORC proteins most likely resides with expression of the RORγt isoform by immature CD4 + /CD8 + cells in the thymus [33,136] and in lymphoid tissue inducer (LTi) cells [34].
Comments: Tretinoin shows selectivity for RORβ within the ROR family [131]. RORα has been suggested to be a nuclear receptor responding to melatonin [151].

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 [100]) 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 [108].

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 [5]. While linoleic acid has been identified as the endogenous ligand for HNF4α its function remains ambiguous [160]. HNF4γ has yet to be paired with an endogenous ligand.

Nuclear hormone receptors → 2C. Testicular receptors
Overview: Testicular receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [5]) have yet to be officially paired with an endogenous ligand, although testicular receptor 4 has been reported to respond to retinoids.

2F. COUP-TF-like receptors
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 [5]) have yet to be officially paired with an endogenous ligand.

3B. Estrogen-related receptors
Nuclear hormone receptors → 3B. Estrogen-related receptors Overview: Estrogen-related receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [5]) 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 [5]) have yet to be officially paired with an endogenous ligand.

Nomenclature
Nerve Growth factor IB Nuclear receptor related 1 Neuron-derived orphan receptor 1

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 [5]) have yet to be officially paired with an endogenous ligand.