Constitutive Androstane Receptor
The constitutive androstane receptor (CAR), a member of the nuclear receptor subfamily 1 (NR1I3- nuclear receptor subfamily 1, group I, member 3), initially identified as a xenosensor (sensor of xenobiotics), is a functionally pleiotropic, liver-enriched transcription factor with roles in various cellular processes and diseases.
Human CAR, first cloned in 1994 (and called MB67 at that point of time), was originally regarded as an “orphan” nuclear receptor, with no apparent endogenous ligand. It is expressed to the highest extent in the liver and small intestine. Additionally, unlike many nuclear receptors requiring the presence of a ligand to activate and cause its translocation from the cytoplasm to the nucleus, CAR, in heterodimerization with 9-cis retinoic acid receptor (RXR), transactivates and exhibits “basal” activity even in the absence of ligand. Hence, it initially came to be known as the “constitutively active receptor.” Later,...
KeywordsLigand Binding Domain Inverse Agonist Constitutive Androstane Receptor Nuclear Receptor Subfamily Brain Tumor Stem Cell
An agent capable of binding to the same receptor binding-site as the agonist but causing a pharmacologically opposite effect as that of the agonist in a constitutively active receptor (i.e., a receptor exhibiting a certain level of intrinsic basal activity). In other words they cause a reduction of the basal expression. Depending on the affinity of the ligand to the receptor, inverse antagonism could be complete or partial.
A member of the nuclear receptor subfamily 1, group I (NR1I2), along with the constitutive androstane receptor (CAR) and vitamin D receptor (VDR). PXR, similar to CAR, has also been predominantly found to be expressed in the liver. It primarily serves as a xenobiotic and steroid hormone sensor. Human PXR was initially reported as a steroid and xenobiotic receptor and hence also called SXR. Along with CAR, PXR shares several similarities in its mechanism of action, along with overlapping roles in many of the physiological and disease processes, including inflammation and cancer.
Nuclear receptors are modular in structure with five-six domains, N to C terminus. These include an N-terminal A/B regulatory region with transcriptional activation function (AF-1) domain, a C region with a DNA-binding domain (DBD), a hinge D region and an E region with a ligand-binding domain (LBD) containing an activation function (AF-2) at its end.
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