Role of cAMP in mediating AHR signaling

Regulation of the nuclear import of many transcription factors represents a step in gene regulation which is crucial for a number of cellular processes. The aryl hydrocarbon receptor (AHR), a basic helix-loop-helix protein of the PAS (PER-ARNT-SIM) family of transcriptional regulators is a cytosol-associated and ligand-activated receptor. The environmental toxin dioxin binds with high affinity to AHR rendering it nuclear and leading to the activation of AHR sensitive genes. However, the fact, that the AHR mediates a large variety of physiological events without the involvement of any known exogenous ligand, including liver and vascular system development, maturation of the immune system, regulation of genes involved in cellular growth, cell differentiation and circadian rhythm, speaks for an important role of AHR in cell biology independent of the presence of an exogenous ligand. Different approaches were applied to study mechanism(s) which render AHR nuclear and design its function in absence of exogenous ligands. We found that AHR is sensitive to cAMP signaling mediated by cAMP-dependent protein kinase (PKA) which fundamentally differs from AHR signaling mediated by the exogenous ligand dioxin. It has been shown that PKA mediated signaling can be confined by compartmentalization of signaling components in microdomains conferring specificity to signaling by the ubiquitous second messenger cAMP. Moreover, A-kinase-anchoring proteins (AKAPs) and newly discovered cAMP receptors, Epac (exchange protein directly activated by cAMP), may give us a further chance to enter into new dimensions of cAMP signal transmissions that potentially may bring us closer to AHR physiology.