Aryl hydrocarbon receptor activation by cAMP vs. dioxin: divergent signaling pathways.
Even before the first vertebrates appeared on our planet, the aryl hydrocarbon receptor (AHR) gene was present to carry out one or more critical life functions. The vertebrate AHR then evolved to take on functions of detecting and responding to certain classes of environmental toxicants. These environmental pollutants include polycyclic aromatic hydrocarbons (e.g., benzo[a]pyrene), polyhalogenated hydrocarbons, dibenzofurans, and the most potent small-molecular-weight toxicant known, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or dioxin). After binding of these ligands, the activated AHR translocates rapidly from the cytosol to the nucleus, where it forms a heterodimer with aryl hydrocarbon nuclear translocator, causing cellular responses that lead to toxicity, carcinogenesis, and teratogenesis. The nuclear form of the activated AHR/aryl hydrocarbon nuclear translocator complex is responsible for alterations in immune, endocrine, reproductive, developmental, cardiovascular, and central nervous system functions whose mechanisms remain poorly understood. Here, we show that the second messenger, cAMP (an endogenous mediator of hormones, neurotransmitters, and prostaglandins), activates the AHR, moving the receptor to the nucleus in some ways that are similar to and in other ways fundamentally different from AHR activation by dioxin. We suggest that this cAMP-mediated activation may reflect the true endogenous function of AHR; disruption of the cAMP-mediated activation by dioxin, binding chronically to the AHR for days, weeks, or months, might be pivotal in the mechanism of dioxin toxicity. Understanding this endogenous activation of the AHR by cAMP may help in developing methods to counteract the toxicity caused by numerous environmental and food-borne toxic chemicals that act via the AHR.
Institute of Toxicology, University of Mainz, Obere Zahlbacher Strasse 67, 55131 Mainz, Germany. oeschb@uni-mainz.de
Barbara
B
Oesch-Bartlomowicz
Andrea
A
Huelster
Oliver
O
Wiss
Patricia
P
Antoniou-Lipfert
Cornelia
C
Dietrich
Michael
M
Arand
Carsten
C
Weiss
Ernesto
E
Bockamp
Franz
F
Oesch
D021581:Active Transport, Cell Nucleus; D000818:Animals; D003994:Bucladesine / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D003247:Conservation of Natural Resources; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D019281:Dimerization; D004147:Dioxins / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D004777:Environment; D004785:Environmental Pollutants / Q000494:pharmacology; D019084:Fluorescent Antibody Technique, Indirect; D017930:Genes, Reporter; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000378:metabolism; D015151:Immunoblotting; D047468:Immunoprecipitation; D008024:Ligands; D051379:Mice; D008856:Microscopy, Fluorescence; D010957:Plasmids / Q000378:metabolism; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D011453:Prostaglandins / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic
D004147:Dioxins; D004785:Environmental Pollutants; D008024:Ligands; D000072317:Polychlorinated Dibenzodioxins; D011453:Prostaglandins; D018336:Receptors, Aryl Hydrocarbon; D049452:Green Fluorescent Proteins; D005576:Colforsin; D003994:Bucladesine; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases