Endocrine Abstracts (2009) 20 PL7

Implications of adrenal hormone pulsatility

Stafford Lightman

University of Bristol, Bristol, UK.

The HPA axis has a massive dynamic response rate. At nadir periods (at night in man and during the day in nocturnal rodents) there is a low level of activity which increases up until the circadian peak. This circadian rhythm is made up of an underlying ultradian rhythm of pulsatile glucocorticoid section, with pulse amplitude increasing from the circadian nadir to the circadian peak. Superimposed on this underlying rhythm is, of course, the stress response which can result in massive peaks of glucocorticoid secretion with high levels lasting much longer than the normal endogenous pulses. Why does the HPA axis have such a complex underlying rhythmicity and is it important for the ability of the organism to show both rapid and prolonged responses to homeostatic stress?

If the ultradian rhythmicity is important, rapid changes in endogenous glucocorticoids must have some rapid effects on cell signalling. We have shown that at the level of the whole animal, rapid changes in glucocorticoid can turn off HPA activity within about 20 min both in the rat and in man. Furthermore, using much lower concentrations of endogenous glucocorticoids we can show that each individual pulse of glucocorticoid results in a distinct translocation of GR from the cytoplasm to the nucleus, binding to promoter sequences of glucocorticoid responsive genes and transcription of pulses of hnRNA and mRNA. Interestingly in the brain there are distinctive time domains for the DNA binding of GR and MR. This provides scope for a digital signalling mechanism in which the frequency of pulses will determine the ratio of GR to MR binding to DNA – in effect an mechanism in which the response depends on the frequency of incoming signals acting on stochastic intranuclear events. Furthermore, it appears that translation of GR from the cytoplasm to the nucleus is not always necessary for these rapid intranuclear events and that there is an endogenous intranuclear cycle of GR activation, DNA binding and dissociation intimately related to chaperones and other accessory intranuclear proteins.

The HPA clearly uses rapid episodic changes to signal through both membrane associated and nuclear receptors. This allows an ability to respond to changes of great temporal and magnitude diversity. The next stage in our enquiries needs to be at the level of how this is reflected in the functional response to HPA signals.

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