Ah Receptor Signaling Pathways

Abstract

The aryl hydrocarbon (Ah) receptor has occupied the attention of toxicologists for over two decades. Interest arose from the early observation that this soluble protein played key roles in the adaptive metabolic response to polycyclic aromatic hydrocarbons and in the toxic mechanism of halogenated dioxins and dibenzofurans. More recent investigations have provided a fairly clear picture of the primary adaptive signaling pathway, from agonist binding to the transcriptional activation of genes involved in the metabolism of xenobiotics. Structure-activity studies have provided an understanding of the pharmacology of this receptor; recombinant DNA approaches have identified the enhancer sequences through which this factor regulates gene expression; and functional analysis of cloned cDNAs has allowed the characterization of the major signaling components in this pathway. Our objective is to review the Ah receptor's role in regulation of xenobiotic metabolism and use this model as a framework for understanding the less well-characterized mechanism of dioxin toxicity. In addition, it is hoped that this information can serve as a model for future efforts to understand an emerging superfamily of related signaling pathways that control biological responses to an array of environmental stimuli.

Structural and Functional Characterization of the Aryl Hydrocarbon Receptor Ligand Binding Domain by Homology Modeling and Mutational Analysis

“…Among the various domains of the AhR that exhibit distinct functional activities (1,(13)(14)(15), we have primarily focused our attention on that of PAS B, one of the two structural repeats (PAS A and PAS B) within the PAS domain, that is involved in both ligand and hsp90 binding. In contrast to the significant amount of information available regarding AhR ligands, essentially nothing is known about the AhR ligand binding domain (LBD) itself.…”

Mixture-specific gene expression in zebrafish ( Danio rerio ) embryos exposed to perfluorooctane sulfonic acid (PFOS), perfluorohexanoic acid (PFHxA) and 3,3′,4,4′,5-pentachlorobiphenyl (PCB126)

“…The binding of AhR-agonist molecules on AhR2 results in the translocation of the complex to the nucleus and to its binding to a regulatory sequence in cyp1a promoter to induce its transcription (Schmidt and Bradfield, 1996). The exacerbate activity of Cyp1a is known to increase the reactive oxygen species content and to cause oxidative stress (Schlezinger et al, 2006) which is highly toxic to the organism.…”

Phosphodiesterases link the aryl hydrocarbon receptor complex to cyclic nucleotide signaling

“…It is a ligand-activated transcription factor known to mediate the cellular effects elicited by xenobiotic compounds, including a wide variety of hydrophobic environmental pollutants such as TCDD (2,3,7,8 tetrachlorodibenzo-p-dioxin). The translated protein exhibits an N-terminal basic helix-loop-helix domain (bHLH) required for DNAbinding and heterodimerization.…”

“…The pattern of cellular functions under control of AHR is quite diverse including detoxification of xenobiotics, inflammatory responses, tissue development and regeneration [1][2][3][4][5]. The AHR can be activated by exogenous compounds such as dioxins, however, endogenous ligands appear to exist and the AHR might be active in the absence of exogenous substances [6][7][8]. The AHR shares many of its mechanisms of action and regulation with other nuclear receptors or ligandactivated transcription factors.…”