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Stafford Lightman"Glucocorticoids like it hot: An hour in the life of the glucocorticoid receptor"

Abstract :


The circadian variation of the hypothalamo-pituitary-adrenal axis is one of the best characterised rhythms in neuroendocrinology.
Less well recognised however, is the fact that this rhythm is made up from an underlying ultradian rhythm of glucocorticoid release, and that it is changes in pulse amplitude in particular that result in circadian variation. The origin of this ultradian rhythmicity has been unclear, but using a non-linear mathematical approach we find that the feedforward:feedback relationship between the pituitary and adrenal cortex is sufficient to explain the underlying oscillations, which in turn respond to altered gain from CRH and AVP. These rhythms encoded by the HPA axis need to be decoded in the tissues – and we can show that each individual pulse of glucocorticoid is followed by a pulse of GR binding to DNA – and indeed to promoter regions of glucocorticoid responsive genes. These pulses are then faithfully followed by pulses of nascent RNA showing gene pulsing in response to ultradian hormone secretion. The size of the pulses at tissue level will depend on the plasma levels of free glucocorticoid which in turn depend on the concentration of CBG and its affinity for cortisol/corticosterone. This affinity depends on tissue temperature so that fever or external sources of heat will have marked effects on glucocorticoid delivery.

Bio
Stafford Lightman is Professor of Medicine at the University of Bristol in the United Kingdom and is Director of the Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology. He started his scientific career working on catecholamines and opioid peptides with Leslie Iversen at the University of Cambridge and provided some of the first data linking opioid peptides with the regulation of neurohypophysial function. At this time he also performed some of the first studies demonstrating the importance of brain stem catecholamine pathways in the regulation of hypothalamic activity. On moving to what is now Imperial College in London, he started to develop his studies on the role of the brain in the regulation of the stress response. He demonstrated the shift from CRH to arginine vasopressin in the control of the hypothalamic-pituitary-adrenal axis during chronic stress, demonstrated and characterised the development of stress hyporesponsiveness during lactation in both rats and man and developed models of immunological activation of the stress response. More recently he has developed the concept of the importance of digital signalling inherent in the pulsatile release of glucocorticoid hormones and has been able to demonstrate the specificity of mineralocorticoid receptor and glucocorticoid receptor responsiveness to rapid changes in levels of circulating glucorticoids.

Stafford Lightman was the founder Editor-in-Chief of the Journal of Neuroendocrinology, a founder Fellow of the Faculty of Medical Sciences, the founder Chairman of the Pituitary Foundation and a Council Member of the Physiological Society. He sits on several Research Councils, Wellcome Trust and European Research Committees and has Chaired the European Union Committee Review of Tertiary Education in East Africa. Professor Lightman also has a major interest in inter-relationships between art and neuroscience and is a frequent speaker on both radio and television in the United Kingdom. 

Selected publications

The crucial role of pulsatile activity of the HPA axis for continuous dynamic equilibration. Lightman SL, Conway-Campbell BL. Nat Rev Neurosci. 2010 Oct;11(10):710-8. Epub 2010 Sep 15.
ACTH-Dependent Ultradian Rhythm of Corticosterone Secretion.Spiga F, Waite EJ, Liu Y, Kershaw YM, Aguilera G, Lightman SL. J Clin Endocrinol Metab. 2011 Mar;96(3):870. No abstract available.

Stavreva DA, Wiench M, John S, Conway-Campbell BL, McKenna MA, Pooley JR, Johnson TA, Voss TC, Lightman SL, Hager GL (2009) Ultradian hormone stimulation induces glucocorticoid receptor-mediated pulses of gene transcription. Nature Cell Biology; 11: 1093-1102 [Medline]
Evuarherhe O, Leggett JD, Waite EJ, Kershaw YM, Atkinson HC, Lightman SL (2009) Organizational role for pubertal androgens on adult hypothalamic-pituitary-adrenal sensitivity to testosterone in the male rat. Journal of Physiology; 587(12): 2977-2985 [Medline]

Marie Pierre Moisan