NR1I3
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1XVP, 1XV9
Identifiers
Aliases	NR1I3, CAR, CAR1, MB67, nuclear receptor subfamily 1 group I member 3
External IDs	OMIM: 603881 MGI: 1346307 HomoloGene: 3759 GeneCards: NR1I3
Gene location (Human) Chr. Chromosome 1 (human)[1] Band 1q23.3 Start 161,229,666 bp[1] End 161,238,244 bp[1]
Gene location (Mouse) Chr. Chromosome 1 (mouse)[2] Band 1 H3|1 79.21 cM Start 171,041,539 bp[2] End 171,048,270 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right lobe of liver nucleus accumbens kidney caudate nucleus gastrocnemius muscle putamen prefrontal cortex ganglionic eminence bone marrow cells left ventricle Top expressed in left lobe of liver duodenum gallbladder entorhinal cortex jejunum urethra male urethra morula lens pharynx More reference expression data BioGPS More reference expression data
Gene ontology Molecular function DNA binding sequence-specific DNA binding RNA polymerase II transcription regulatory region sequence-specific DNA binding DNA-binding transcription factor activity DNA-binding transcription activator activity, RNA polymerase II-specific transcription coactivator activity zinc ion binding metal ion binding steroid hormone receptor activity nuclear receptor activity DNA-binding transcription factor activity, RNA polymerase II-specific transcription cis-regulatory region binding transcription factor binding nuclear receptor coactivator activity signaling receptor activity Cellular component cytoplasm cytosol nucleoplasm cytoskeleton nucleus RNA polymerase II transcription regulator complex Biological process regulation of transcription, DNA-templated transcription, DNA-templated transcription initiation from RNA polymerase II promoter negative regulation of transcription, DNA-templated signal transduction positive regulation of transcription by RNA polymerase II steroid hormone mediated signaling pathway androgen receptor signaling pathway intracellular receptor signaling pathway multicellular organism development cell differentiation Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 9970 12355 Ensembl ENSG00000143257 ENSMUSG00000005677 UniProt Q14994 Q6GZ81 O35627 RefSeq (mRNA) NM_001077469 NM_001077470 NM_001077471 NM_001077472 NM_001077473 NM_001077474 NM_001077475 NM_001077476 NM_001077477 NM_001077478 NM_001077479 NM_001077480 NM_001077481 NM_001077482 NM_005122 NM_001243062 NM_001243063 NM_009803 RefSeq (protein) NP_001070937 NP_001070938 NP_001070939 NP_001070940 NP_001070941 NP_001070942 NP_001070943 NP_001070944 NP_001070945 NP_001070946 NP_001070947 NP_001070948 NP_001070949 NP_001070950 NP_005113 NP_001229991 NP_001229992 NP_033933 Location (UCSC) Chr 1: 161.23 – 161.24 Mb Chr 1: 171.04 – 171.05 Mb PubMed search [3] [4]
Wikidata
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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.^[5] 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.^[6] 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.^[7] More recently, dehydroepiandrosterone (DHEA), also an androstane, has been found to be an endogenous agonist of the CAR.^[8]

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.^[9] Ligands binding to CAR include bilirubin, a variety of foreign compounds, steroid hormones, and prescription drugs.^[10]

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.^[11] 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).^[12]

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.^[13]

The consensus sequence of PBREM, containing direct repeat-4 motifs, was found to be conserved in mouse, rat and human 'Cyp2b' genes.^[14][15][16]

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.^[19][20] 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.^[21]

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.^[20]

References

Further reading

External links

• constitutive+androstane+receptor at the U.S. National Library of Medicine Medical Subject Headings (MeSH)

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