The constitutive androstane receptor and pregnane X receptor in the brain

Abstract

Since their discovery, the orphan nuclear receptors constitutive androstane receptor (CAR;NR1I3) and pregnane X receptor (PXR;NR1I2) have been regarded as master regulators of drug disposition and detoxification mechanisms. They regulate the metabolism and transport of endogenous mediators and xenobiotics in organs including the liver, intestine and brain. However, with proposals of new physiological functions for NR1I3 and NR1I2, there is increasing interest in the role of these receptors in influencing brain function. This review will summarise key findings regarding the expression and function of NR1I3 and NR1I2 in the brain, hereby highlighting the need for further research in this field.

FIGURE 1

Known biological actions of NR1I3 (CAR) and NR1I2 (PXR). Since both nuclear receptors are ubiquitously expressed in organs and tissues of mammalians, they regulate the expression of proteins involved in metabolism and transport of nutrients, endogenous mediators and xenobiotics in a tissue‐dependent manner. Furthermore, NR1I3 and NR1I2 can also influence biological processes including inflammation and apoptosis through protein‐protein interactions. Recent research have demonstrated that in the brain, apart from their role in some of the above‐mentioned processes, NR1I3 and NR1I2 may participate in complex functions such as behaviour

FIGURE 2

Comparison of the downstream events of the NR1I3 (CAR) and NR1I2 (PXR) signalling pathways in liver and brain. Most of the research aiming to characterise the signalling pathways of NR1I3 and NR1I2 has been conducted in liver, whilst organs such as the brain are much less studied. This issue is particularly important as brain endothelial cells and neurons express both receptors and the response to the ligand‐based activation of NR1I3 and NR1I2 appears vary amongst areas of the brain. This outcome is consistent with the tissue‐dependent effects of