Phosphodiesterases link the aryl hydrocarbon receptor complex to cyclic nucleotide signaling

The aryl hydrocarbon receptor (AHR) is a major transcription factor regulated by different mechanisms. The classical view of AHR activation by xenobiotics needs to be amended by recent findings on the regulation of AHR by endogenous ligands and by crosstalk with other signaling pathways. In the cytosol the AHR recruits a large number of binding partners, including HSP90, p23, XAP2 and the ubiquitin ligases cullin 4B and CHIP. Furthermore, XAP2 binds the cyclic nucleotide phosphodiesterases PDE2A and PDE4A5. PDE2A inhibits nuclear translocation of AHR suggesting an important regulatory role of cyclic nucleotides in AHR trafficking. Signaling involving cAMP is organized in subcellular compartments and a distinct cAMP compartment might be required for proper AHR mobility and function. We conclude that the AHR complex integrates ligand binding and cyclic nucleotide signaling to generate an adequate transcriptional response.