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

Alexey Kolodkin, Nilgun Sahin, Anna Phillips, Steve R. Hood, Frank J. Bruggeman, Hans V. Westerhoff and Nick Plant ()
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Alexey Kolodkin: Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Campus Belval
Nilgun Sahin: Molecular Cell Physiology, Netherlands Institute of Systems Biology, VU University Amsterdam, de Boelelaan 1085, NL-1081 HV Amsterdam, The Netherlands
Anna Phillips: Centre for Toxicology, Faculty of Health and Medical Sciences, University of Surrey
Steve R. Hood: GOLD, GlaxoSmithKline, Park Road
Frank J. Bruggeman: Molecular Cell Physiology, Netherlands Institute of Systems Biology, VU University Amsterdam, de Boelelaan 1085, NL-1081 HV Amsterdam, The Netherlands
Hans V. Westerhoff: Molecular Cell Physiology, Netherlands Institute of Systems Biology, VU University Amsterdam, de Boelelaan 1085, NL-1081 HV Amsterdam, The Netherlands
Nick Plant: Centre for Toxicology, Faculty of Health and Medical Sciences, University of Surrey

Nature Communications, 2013, vol. 4, issue 1, 1-8

Abstract: Abstract 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.

Date: 2013
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DOI: 10.1038/ncomms2799

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