Optimization of stress response through the nuclear receptor-mediated cortisol signalling network

• Published in: Nature communications 2013-04, Vol.4 (1), p.1792-1792, Article 1792
• Main Authors: Kolodkin, Alexey, Sahin, Nilgun, Phillips, Anna, Hood, Steve R., Bruggeman, Frank J., Westerhoff, Hans V., Plant, Nick
• Format: Article
• Language: English
• Subjects: 631/553; 631/80/86/2366; Adaptation, Physiological; Feedback, Physiological; Gene Regulatory Networks; Humanities and Social Sciences; Humans; Hydrocortisone - metabolism; Ligands; Models, Biological; multidisciplinary; Pregnane X Receptor; Receptors, Cytoplasmic and Nuclear - metabolism; Receptors, Glucocorticoid - metabolism; Receptors, Steroid - metabolism; Reproducibility of Results; Science; Science (multidisciplinary); Signal Transduction - genetics; Stress, Physiological - genetics
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms2799

It is an accepted paradigm that extended stress predisposes an individual to pathophysiology. However, the biological adaptations to minimize this risk are poorly understood. Using a computational model based upon realistic kinetic parameters we are able to reproduce the interaction of the stress hormone cortisol with its two nuclear receptors, the high-affinity glucocorticoid receptor and the low-affinity pregnane X-receptor. We demonstrate that regulatory signals between these two nuclear receptors are necessary to optimize the body’s response to stress episodes, attenuating both the magnitude and duration of the biological response. In addition, we predict that the activation of pregnane X-receptor by multiple, low-affinity endobiotic ligands is necessary for the significant pregnane X-receptor-mediated transcriptional response observed following stress episodes. This integration allows responses mediated through both the high and low-affinity nuclear receptors, which we predict is an important strategy to minimize the risk of disease from chronic stress. Stress causes cortisol release and this is associated with the development of pathophysiology. Plant and colleagues use a computational model to reproduce the interaction of cortisol with its two nuclear receptors, and reveal how feed-forward and feed-back loops coordinate adaptation to repeated stress.