Constitutive androstane receptor

Constitutive androstane receptor

Nuclear receptor subfamily 1, group I, member 3
PDB rendering based on 1xv9.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols  ; CAR; CAR1; MB67
External IDs IUPHAR: ChEMBL: GeneCards:
RNA expression pattern
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)
PubMed search

The constitutive androstane receptor (CAR) also known as nuclear receptor subfamily 1, group I, member 3 is a protein that in humans is encoded by the NR1I3 gene.[1] CAR is a member of the nuclear receptor superfamily and along with pregnane X receptor (PXR) functions as a sensor of endobiotic and xenobiotic substances. In response, expression of proteins responsible for the metabolism and excretion of these substances is upregulated.[2] Hence, CAR and PXR play a major role in the detoxification of foreign substances such as drugs.

Androstenol and several isomers of androstanol, androstanes, are endogenous antagonists of the CAR, and despite their nature as antagonists, were the basis for the naming of the receptor.[3] More recently, dehydroepiandrosterone (DHEA), also an androstane, has been found to be an endogenous agonist of the CAR.[4]

Contents

  • Function 1
  • Activation mechanism 2
    • Direct activation by TCPOBOP 2.1
    • Indirect activation by PB 2.2
  • References 3
  • Further reading 4
  • External links 5

Function

CAR is a member of the nuclear receptor superfamily, and is a key regulator of xenobiotic and endobiotic metabolism. Unlike most nuclear receptors, this transcriptional regulator is constitutively active in the absence of ligand and is regulated by both agonists and inverse agonists. Ligand binding results in translocation of CAR from the cytosol into the nucleus, where the protein can bind to specific DNA sites, called response elements. Binding occurs both as a monomer and together with the retinoid X receptor (RXR) resulting in activation or repression of target gene transcription. CAR-regulated genes are involved in drug metabolism and bilirubin clearance. Examples for CAR-regulated genes are members of the CYP2B, CYP2C, and CYP3A subfamilies, sulfotransferases, and glutathione-S-transferases.[5] Ligands binding to CAR include bilirubin, a variety of foreign compounds, steroid hormones, and prescription drugs. [6]

Activation mechanism

Phosphorylated CAR forms a multiprotein complex with the heat shock protein 90 (hsp90) and the cytoplasmic CAR retention protein (CCRP) which keep CAR in the cytosol thereby inactivating it. [7] CAR can be activated in two ways: by direct binding of a ligand (e.g. TCPOBOP) or indirect regulation by phenobarbital (PB), a common seizure medication, facilitating the dephosphorylation of CAR through protein phosphatase 2 (PP2A) (Fig. 1). Both lead to the release of CAR from the multiprotein complex and its translocation into the nucleus. Here, CAR forms a heterodimer with retinoid X receptor (RXR) and interacts with the phenobarbital-responsive enhancer module (PBREM), a distal enhancer activating transcription of CAR target genes. [8]

The consensus sequence of PBREM, containing direct repeat-4 motifs, was found to be conserved in mouse, rat and human 'Cyp2b' genes.[9][10][11]

Direct activation by TCPOBOP

1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) is thought bind directly to CAR, thus inducing its translocation into the nucleus.[12]

Indirect activation by PB

Phenobarbital, a widely used anticonvulsant, is used as a model ligand for indirect CAR activation. Some findings[13]

[14] suggest that PB activates CAR, by inducing the dephosphorylation of CAR through PP2A. How PP2A is activated remains unclear, but different mechanisms have been described.

The recruitment of PP2A has been shown to be mediated by the multiprotein complex.8 As PB is involved in the activation of AMP-activated protein kinase, it has been suggested that AMPK activates PP2A.[15]

Alternatively, PP2A might be activated through another pathway including the epidermal growth factor receptor (EGFR) and the receptor for activated C kinase 1 (RACK1). In the absence of PB, the epidermal growth factor (EGF) binds to EGFR, thereby activating the steroid receptor coactivator-1 (Src1), which in turn phosphorylates RACK1. Upon PB-exposure, PB binds competitively to EGFR and thus leads to inactivation of Src1. This results in a dephosphorylation of RACK1, which can subsequently stimulate PP2A to activate CAR. [14]

Figure 1 - Activation mechanisms of CAR: Inactivated CAR is retained in the cytosol. Upon binding of TCPOBOP, CAR gets dephosphorylated by PP2A and translocates into the nucleus. Here, it forms a complex with RXR and binds to the PB-responsive enhancer module. Another possibility to activate CAR is the indirect activation through PB. PB binds competitively to EGFR, thus inducing the dephosphorylation of RACK-1. RACK-1 then stimulates PP2A to dephosphorylate CAR, which is then translocated into the nucleus.

References

  1. ^ Baes M, Gulick T, Choi HS, Martinoli MG, Simha D, Moore DD (March 1994). "A new orphan member of the nuclear hormone receptor superfamily that interacts with a subset of retinoic acid response elements". Mol. Cell. Biol. 14 (3): 1544–52.  
  2. ^ Wada T, Gao J, Xie W (August 2009). "PXR and CAR in energy metabolism". Trends Endocrinol. Metab. 20 (6): 273–9.  
  3. ^ Nicholas A. Meanwell (8 December 2014). Tactics in Contemporary Drug Design. Springer. pp. 182–.  
  4. ^ Kohalmy K, Tamási V, Kóbori L, Sárváry E, Pascussi JM, Porrogi P, et al. (2007). "Dehydroepiandrosterone induces human CYP2B6 through the constitutive androstane receptor". Drug Metab. Dispos. 35 (9): 1495–501.  
  5. ^ Ueda A, Hamadeh HK, Webb HK, Yamamoto Y, Sueyoshi T, Afshari CA, Lehmann JM, Negishi M (2002). "Diverse roles of the nuclear orphan receptor CAR in regulating hepatic genes in response to phenobarbital". Mol. Pharmacol. 61 (1): 1–6.  
  6. ^ "Entrez Gene: NR1I3 nuclear receptor subfamily 1, group I, member 3". 
  7. ^ Kodama S, Negishi M; Negishi, M. (2006). "Phenobarbital confers its diverse effects by activating the orphan nuclear receptor car.". Drug Metab. Rev. 38: 75–87.  
  8. ^ Kawamoto T, Sueyoshi T, Zelko I, Moore R, Washburn K, Negishi M (1999). "Phenobarbital-responsive nuclear translocation of the receptor CAR in induction of the CYP2B gene". Mol. Cell. Biol. 19 (9): 6318–22.  
  9. ^ Honkakoski P, Moore R, Washburn KA, Negishi M (1998). "Activation by diverse xenochemicals of the 51-base pair phenobarbital-responsive enhancer module in the CYP2B10 gene". Mol. Pharmacol. 53 (4): 597–601.  
  10. ^ Sueyoshi T, Kawamoto T, Zelko I, Honkakoski P, Negishi M (1999). "The repressed nuclear receptor CAR responds to phenobarbital in activating the human CYP2B6 gene". J. Biol. Chem. 274 (10): 6043–6.  
  11. ^ Mäkinen J, Frank C, Jyrkkärinne J, Gynther J, Carlberg C, Honkakoski P (August 2002). "Modulation of mouse and human phenobarbital-responsive enhancer module by nuclear receptors". Mol. Pharmacol. 62 (2): 366–78.  
  12. ^ Tzameli I, Pissios P, Schuetz EG, Moore DD (May 2000). "The xenobiotic compound 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene is an agonist ligand for the nuclear receptor CAR". Mol. Cell. Biol. 20 (9): 2951–8.  
  13. ^ Yoshinari K, Kobayashi K, Moore R, Kawamoto T, Negishi M (July 2003). "Identification of the nuclear receptor CAR:HSP90 complex in mouse liver and recruitment of protein phosphatase 2A in response to phenobarbital". FEBS Lett. 548 (1-3): 17–20.  
  14. ^ a b Mutoh S, Sobhany M, Moore R, Perera L, Pedersen L, Sueyoshi T, Negishi M (2013). "Phenobarbital Indirectly Activates the Constitutive Active Androstane Receptor (CAR) by Inhibition of Epidermal Growth Factor Receptor Signaling.". Sci. Signal. 6: ra31.  
  15. ^ Rencurel F, Stenhouse A, Hawley SA, Friedberg T, Hardie DG, Sutherland C, Wolf CR (2005). "AMP-activated protein kinase mediates phenobarbital induction of CYP2B gene expression in hepatocytes and a newly derived human hepatoma cell line.". J. Biol. Chem. 280: 4367–4373.  

Further reading

  • Masuno M, Shimozawa N, Suzuki Y, Kondo N, Orii T, Tsukamoto T, Osumi T, Fujiki Y, Imaizumi K, Kuroki Y (1994). "Assignment of the human peroxisome assembly factor-1 gene (PXMP3) responsible for Zellweger syndrome to chromosome 8q21.1 by fluorescence in situ hybridization". Genomics 20 (1): 141–2.  
  • Choi HS, Seol W, Moore DD (1996). "A component of the 26S proteasome binds on orphan member of the nuclear hormone receptor superfamily". J. Steroid Biochem. Mol. Biol. 56 (1–6 Spec No): 23–30.  
  • Seol W, Choi HS, Moore DD (1996). "An orphan nuclear hormone receptor that lacks a DNA binding domain and heterodimerizes with other receptors". Science 272 (5266): 1336–9.  
  • Choi HS, Chung M, Tzameli I, Simha D, Lee YK, Seol W, Moore DD (1997). "Differential transactivation by two isoforms of the orphan nuclear hormone receptor CAR". J. Biol. Chem. 272 (38): 23565–71.  
  • Seol W, Hanstein B, Brown M, Moore DD (1998). "Inhibition of estrogen receptor action by the orphan receptor SHP (short heterodimer partner)". Mol. Endocrinol. 12 (10): 1551–7.  
  • Forman BM, Tzameli I, Choi HS, Chen J, Simha D, Seol W, Evans RM, Moore DD (1998). "Androstane metabolites bind to and deactivate the nuclear receptor CAR-beta". Nature 395 (6702): 612–5.  
  • Gonzalez MM, Carlberg C (2002). "Cross-repression, a functional consequence of the physical interaction of non-liganded nuclear receptors and POU domain transcription factors". J. Biol. Chem. 277 (21): 18501–9.  
  • Min G, Kim H, Bae Y, Petz L, Kemper JK (2002). "Inhibitory cross-talk between estrogen receptor (ER) and constitutively activated androstane receptor (CAR). CAR inhibits ER-mediated signaling pathway by squelching p160 coactivators". J. Biol. Chem. 277 (37): 34626–33.  
  • Goodwin B, Hodgson E, D'Costa DJ, Robertson GR, Liddle C (2002). "Transcriptional regulation of the human CYP3A4 gene by the constitutive androstane receptor". Mol. Pharmacol. 62 (2): 359–65.  
  • Ferguson SS, LeCluyse EL, Negishi M, Goldstein JA (2002). "Regulation of human CYP2C9 by the constitutive androstane receptor: discovery of a new distal binding site". Mol. Pharmacol. 62 (3): 737–46.  
  • Zhang J, Huang W, Chua SS, Wei P, Moore DD (2002). "Modulation of acetaminophen-induced hepatotoxicity by the xenobiotic receptor CAR". Science 298 (5592): 422–4.  
  • Chang TK, Bandiera SM, Chen J (2003). "Constitutive androstane receptor and pregnane X receptor gene expression in human liver: interindividual variability and correlation with CYP2B6 mRNA levels". Drug Metab. Dispos. 31 (1): 7–10.  
  • Pascussi JM, Busson-Le Coniat M, Maurel P, Vilarem MJ (2003). "Transcriptional analysis of the orphan nuclear receptor constitutive androstane receptor (NR1I3) gene promoter: identification of a distal glucocorticoid response element". Mol. Endocrinol. 17 (1): 42–55.  
  • Shiraki T, Sakai N, Kanaya E, Jingami H (2003). "Activation of orphan nuclear constitutive androstane receptor requires subnuclear targeting by peroxisome proliferator-activated receptor gamma coactivator-1 alpha. A possible link between xenobiotic response and nutritional state". J. Biol. Chem. 278 (13): 11344–50.  
  • Maglich JM, Parks DJ, Moore LB, Collins JL, Goodwin B, Billin AN, Stoltz CA, Kliewer SA, Lambert MH, Willson TM, Moore JT (2003). "Identification of a novel human constitutive androstane receptor (CAR) agonist and its use in the identification of CAR target genes". J. Biol. Chem. 278 (19): 17277–83.  
  • Xie W, Yeuh MF, Radominska-Pandya A, Saini SP, Negishi Y, Bottroff BS, Cabrera GY, Tukey RH, Evans RM (2003). "Control of steroid, heme, and carcinogen metabolism by nuclear pregnane X receptor and constitutive androstane receptor". Proc. Natl. Acad. Sci. U.S.A. 100 (7): 4150–5.  
  • Huang W, Zhang J, Chua SS, Qatanani M, Han Y, Granata R, Moore DD (2003). "Induction of bilirubin clearance by the constitutive androstane receptor (CAR)". Proc. Natl. Acad. Sci. U.S.A. 100 (7): 4156–61.  
  • Auerbach SS, Ramsden R, Stoner MA, Verlinde C, Hassett C, Omiecinski CJ (2003). "Alternatively spliced isoforms of the human constitutive androstane receptor". Nucleic Acids Res. 31 (12): 3194–207.  

External links

This article incorporates text from the United States National Library of Medicine, which is in the public domain.