Constitutive androstane receptor

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

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 is_associated_with::agonists and is_associated_with::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 is_associated_with::retinoid X receptor (RXR) resulting in activation or repression of target gene transcription. CAR-regulated genes are involved in drug metabolism and is_associated_with::bilirubin clearance. Examples for CAR-regulated genes are members of the CYP2B, CYP2C, and CYP3A subfamilies, sulfotransferases, and glutathione-S-transferases. Ligands binding to CAR include bilirubin, a variety of foreign compounds, steroid hormones, and prescription drugs.

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. CAR can be activated in two ways: by direct binding of a ligand (e.g. TCPOBOP) or indirect regulation by is_associated_with::phenobarbital (PB), a common seizure medication, facilitating the dephosphorylation of CAR through is_associated_with::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 is_associated_with::retinoid X receptor (RXR) and interacts with the phenobarbital-responsive enhancer module (PBREM), a distal enhancer activating transcription of CAR target genes. The consensus sequence of PBREM, containing direct repeat-4 motifs, was found to be conserved in mouse, rat and human 'Cyp2b' genes.

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.

Indirect activation by PB
Phenobarbital, a widely used is_associated_with::anticonvulsant, is used as a model ligand for indirect CAR activation. Some findings

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 is_associated_with::AMP-activated protein kinase, it has been suggested that AMPK activates PP2A. Alternatively, PP2A might be activated through another pathway including the is_associated_with::epidermal growth factor receptor (EGFR) and the receptor for activated C kinase 1 (RACK1). In the absence of PB, the is_associated_with::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.