Biology:Constitutive androstane receptor

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Short description: Protein-coding gene in humans


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example


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 acting as antagonists, were the basis for the naming of this receptor.[3] More recently, dehydroepiandrosterone (DHEA), also an androstane, has been found to be an endogenous agonist of the CAR.[4]

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).[8]

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.[9]

The consensus sequence of PBREM, containing direct repeat-4 motifs, was found to be conserved in mouse, rat and human 'Cyp2b' genes.[10][11][12]

Direct activation

1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) is thought to bind directly to mouse CAR, thus inducing its translocation into the nucleus.[13] TCPOBOP does not bind to human CAR and hence has no effect on it. Human CAR can be activated by CITCO (6-(4-chlorophenyl)imidazo(2,1-b)(1,3)thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime).[14]

Indirect activation

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.

Phenobarbital (PB), a widely used anticonvulsant, is used as a model ligand for indirect CAR activation. PB activates CAR, by inducing the dephosphorylation of CAR through PP2A. How PP2A is activated remains unclear, but several different mechanisms have been proposed.[15][16] The recruitment of PP2A has been shown to be mediated by the multiprotein complex. As PB is involved in the activation of AMP-activated protein kinase, it has been suggested that AMPK activates PP2A.[17]

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.[16]

References

  1. ↑ "A new orphan member of the nuclear hormone receptor superfamily that interacts with a subset of retinoic acid response elements". Molecular and Cellular Biology 14 (3): 1544–52. Mar 1994. doi:10.1128/mcb.14.3.1544. PMID 8114692. 
  2. ↑ "PXR and CAR in energy metabolism". Trends in Endocrinology and Metabolism 20 (6): 273–9. Aug 2009. doi:10.1016/j.tem.2009.03.003. PMID 19595610. 
  3. ↑ Nicholas A. Meanwell (8 December 2014). Tactics in Contemporary Drug Design. Springer. pp. 182–. ISBN 978-3-642-55041-6. https://books.google.com/books?id=j2HEBQAAQBAJ&pg=PA182. 
  4. ↑ "Dehydroepiandrosterone induces human CYP2B6 through the constitutive androstane receptor". Drug Metab. Dispos. 35 (9): 1495–501. 2007. doi:10.1124/dmd.107.016303. PMID 17591676. 
  5. ↑ "Diverse roles of the nuclear orphan receptor CAR in regulating hepatic genes in response to phenobarbital". Molecular Pharmacology 61 (1): 1–6. Jan 2002. doi:10.1124/mol.61.1.1. PMID 11752199. 
  6. ↑ "Entrez Gene: NR1I3 nuclear receptor subfamily 1, group I, member 3". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=9970. 
  7. ↑ "Phenobarbital confers its diverse effects by activating the orphan nuclear receptor car". Drug Metabolism Reviews 38 (1–2): 75–87. 2006. doi:10.1080/03602530600569851. PMID 16684649. https://zenodo.org/record/1234443. 
  8. ↑ Men, Shuaiqian; Wang, Hongbing (2023). "Phenobarbital in Nuclear Receptor Activation: An Update" (in en). Drug Metabolism and Disposition 51 (2): 210–218. doi:10.1124/dmd.122.000859. ISSN 0090-9556. PMID 36351837. 
  9. ↑ "Phenobarbital-responsive nuclear translocation of the receptor CAR in induction of the CYP2B gene". Molecular and Cellular Biology 19 (9): 6318–22. Sep 1999. doi:10.1128/mcb.19.9.6318. PMID 10454578. 
  10. ↑ "Activation by diverse xenochemicals of the 51-base pair phenobarbital-responsive enhancer module in the CYP2B10 gene". Molecular Pharmacology 53 (4): 597–601. Apr 1998. doi:10.1124/mol.53.4.597. PMID 9547348. 
  11. ↑ "The repressed nuclear receptor CAR responds to phenobarbital in activating the human CYP2B6 gene". The Journal of Biological Chemistry 274 (10): 6043–6. Mar 1999. doi:10.1074/jbc.274.10.6043. PMID 10037683. 
  12. ↑ "Modulation of mouse and human phenobarbital-responsive enhancer module by nuclear receptors". Molecular Pharmacology 62 (2): 366–78. Aug 2002. doi:10.1124/mol.62.2.366. PMID 12130690. 
  13. ↑ "The xenobiotic compound 1,4-bis[2-(3,5-dichloropyridyloxy)benzene is an agonist ligand for the nuclear receptor CAR"]. Molecular and Cellular Biology 20 (9): 2951–8. May 2000. doi:10.1128/MCB.20.9.2951-2958.2000. PMID 10757780. 
  14. ↑ "Identification of a novel human constitutive androstane receptor (CAR) agonist and its use in the identification of CAR target genes". The Journal of Biological Chemistry 278 (19): 17277–83. May 2003. doi:10.1074/jbc.M300138200. PMID 12611900. 
  15. ↑ "Identification of the nuclear receptor CAR:HSP90 complex in mouse liver and recruitment of protein phosphatase 2A in response to phenobarbital". FEBS Letters 548 (1–3): 17–20. Jul 2003. doi:10.1016/s0014-5793(03)00720-8. PMID 12885400. 
  16. ↑ 16.0 16.1 "Phenobarbital indirectly activates the constitutive active androstane receptor (CAR) by inhibition of epidermal growth factor receptor signaling". Science Signaling 6 (274): ra31. May 2013. doi:10.1126/scisignal.2003705. PMID 23652203. 
  17. ↑ "AMP-activated protein kinase mediates phenobarbital induction of CYP2B gene expression in hepatocytes and a newly derived human hepatoma cell line". The Journal of Biological Chemistry 280 (6): 4367–73. Feb 2005. doi:10.1074/jbc.M412711200. PMID 15572372. 

Further reading

External links

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




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