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

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.

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

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 [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 (T 4 ) 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].  Agonists dextrothyroxine [19] dextrothyroxine [19] Selective agonists -sobetirome [24,128] 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 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.

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 [1,7]) have yet to be officially paired with an endogenous ligand, but are thought to be activated by heme.
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
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 [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].

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 [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].

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 [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.

Nuclear hormone receptors → 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.  Comments Gene disruption is perinatally lethal [118]. Gene disruption is embryonically lethal [115]. Gene disruption impairs CNS development [151].

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 [7]) 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 [7]) have yet to be officially paired with an endogenous ligand.  ) 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 [7]) have yet to be officially paired with an endogenous ligand.   [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].

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].
-Comments: [ 3 H]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).