And Now for Something Completely Different: Diversity in Ligand-Dependent Activation of Ah Receptor Responses

Abstract

Ligand-dependent activation of the Ah receptor (AhR) can result in an extremely diverse spectrum of biological and toxic effects that occur in a ligand-, species- and tissue-specific manner. While the classical mechanism of AhR-dependent signal transduction is directly related to its ability to modulate gene expression, the dramatic diversity in responses observed following AhR activation or inhibition is inconsistent with a single molecular mechanism of AhR action. Recent studies have revealed that key molecular events underlying the AhR signaling pathway are significantly more varied and complex than previously established, and the specificity and diversity in AhR response can be selectively modulated by a variety of factors. Here we describe new insights into the mechanistic diversity in AhR signal transduction that can contribute to ligand-, species- and tissue-specific differences in AhR reponse.

Keywords: Ah Receptor; AhR; Ligand Binding; Ligand Specificity; TCDD; Toxicity.

Figure 1

Multiple mechanisms by which a specific ligand-activated AhR can stimulate gene expression. In the classical mechanism of AhR action, ligand binding stimulates AhR nuclear translocation, dimerization with the ARNT protein and the binding of the ligand:AhR:ARNT complex to its DNA binding site (the DRE) stimulates gene expression. However, the dimerization of liganded AhR with other proteins (e.g., KLF6 or RelB) results in the formation of unique protein complexes that bind to distinctly different DNA recognition sites (e.g., a ncXRE or RelBAhRE, respectively) to regulate subsets of genes not regulated by the AhR:ARNT complex. Whether ligand bound AhRs can interact with additional DNA binding partners remains to be determined, but is a possibility. In addition to multiple heterodimers, the AhR has also been observed to bind to other nuclear protein complexes (e.g., estrogen receptor (ER) dimers) and function as a coactivator, enhancing gene expression by these transcription factors.

Figure 2

Ligand-selective differences in AhR-dependent gene expression. Binding and activation of the AhR by structurally diverse AhR ligands could produce significant differences in the overall structure of the AhR and/or its dimerization partner that result in recruitment of distinctly different coactivators to the DNA bound AhR complex and differential gene expression. Although this figure only depicts an alteration in the structure of the AhR, ligand-selective structural changes could also occur in the ARNT protein, or in any other protein(s) to which the AhR is bound (such as KLF6 or RelB (see Figure 1)), facilitating differential coactivator recruitment by a greater diversity of ligand-activated AhR complexes and even a greater diversity in gene expression responses.

Figure 3

Overall mechanisms by which structurally diverse AhR ligands can contribute to ligand-selective differences in AhR-dependent gene expression and toxicity. See text for details.