Mechanisms of xenobiotic receptor activation: Direct vs. indirect

Abstract

The so-called xenobiotic receptors (XRs) have functionally evolved into cellular sensors for both endogenous and exogenous stimuli by regulating the transcription of genes encoding drug-metabolizing enzymes and transporters, as well as those involving energy homeostasis, cell proliferation, and/or immune responses. Unlike prototypical steroid hormone receptors, XRs are activated through both direct ligand-binding and ligand-independent (indirect) mechanisms by a plethora of structurally unrelated chemicals. This review covers research literature that discusses direct vs. indirect activation of XRs. A particular focus is centered on the signaling control of the constitutive androstane receptor (CAR), the pregnane X receptor (PXR) and the aryl hydrocarbon receptor (AhR). We expect that this review will shed light on both the common and distinct mechanisms associated with activation of these three XRs.

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“…Rather, CAR is phosphorylated at steady-state and sequestered in a multiprotein cytoplasmic complex comprised of heat shock protein 90 (Hsp90), Hsp70 and the cytoplasmic CAR retention protein (CCRP). 143 Release of CAR from this inhibitory complex, and subsequent nuclear translocation, is triggered by either direct binding of small molecule 'super-agonists' (e.g., the phenobarbital derivative agonist, 4-bis [2-(3,5-dichloropyridyloxy)]benzene [TCPOBOP]) 144 or by a poorly understood indirect pathway that stems from transmembrane receptors and that induces protein phosphatase 2A (PP2A)-mediated CAR dephosphorylation; this indirect activation of CAR occurs in the presence of numerous pharmaceutical compounds (e.g., phenobarbital) as well as hydrophobic BAs, such as LCA. 86,143,[145][146][147][148] Another distinctive feature of CAR (vis-à-vis most other nuclear receptors) is that CAR displays constitutive (i.e., ligand-independent) transcriptional activity, due to a truncated Cterminal activation function 2 (AF2) motif in the LBD that stables a transcriptionally active conformation.…”

“…143 Release of CAR from this inhibitory complex, and subsequent nuclear translocation, is triggered by either direct binding of small molecule 'super-agonists' (e.g., the phenobarbital derivative agonist, 4-bis [2-(3,5-dichloropyridyloxy)]benzene [TCPOBOP]) 144 or by a poorly understood indirect pathway that stems from transmembrane receptors and that induces protein phosphatase 2A (PP2A)-mediated CAR dephosphorylation; this indirect activation of CAR occurs in the presence of numerous pharmaceutical compounds (e.g., phenobarbital) as well as hydrophobic BAs, such as LCA. 86,143,[145][146][147][148] Another distinctive feature of CAR (vis-à-vis most other nuclear receptors) is that CAR displays constitutive (i.e., ligand-independent) transcriptional activity, due to a truncated Cterminal activation function 2 (AF2) motif in the LBD that stables a transcriptionally active conformation. 149 Nuclear CAR trans-activates target gene expression by binding to cognate DNA regulatory elements either as a monomer or as a heterodimer with retinoid X receptor (RXRα; encoded by NR2B1), 149,150 whereas constitutive CAR activity is inhibited by the binding of androstanes, such as 5α-Androstan-3β-ol.…”

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“…In the cytosol, NR1I3 and NR1I2 are bound to a chaperone protein complex composed of the heat shock protein 90 and the NR1I3 retention protein (Mackowiak & Wang, 2016;Wang, Ong, Chai, & Chen, 2012). Upon activation, NR1I2 and NR1I3 are released from this protein complex and translocate to the nucleus to form a heterodimer with the α, β, γ isoforms of the retinoid X receptor (RXR; NR2B) (Koutsounas et al, 2015).…”

“…Although NR1I2 and NR1I3 are activated by direct ligand binding, evidence suggests that both receptors can be activated via an indirect mechanism. Indirect activation of NR1I3 involves the activation of the ERK (ERK1/2) and MAPK signalling pathways (Mackowiak & Wang, 2016). The mechanism for indirect activation of NR1I2 remains elusive, but studies propose that the cyclin-dependent kinase signalling pathway may be involved (Dong, Lin, Wu, & Chen, 2010;Lin et al, 2008).…”

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“…(6) 'Mechanism of xenobiotic receptor activation: Direct vs indirect' [20], where the authors focus on the nuclear receptor (NR; remember that SXR = PXR also goes by the name NR1/2 = Nuclear Receptor 1/2) and its mode of activation, via pairing with a different nuclear receptor partner (activators/inhibitors, such as RXR, CCRP, NCOR, SMRT and several others). PXR may also be activated indirectly, which contributes to a meticulous and intricate regulatory system.…”