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This version published online on August 9, 2007
Endocrinology, doi:10.1210/en.2007-0585
A more recent version of this article appeared on November 1, 2007
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Submitted on May 3, 2007
Accepted on August 1, 2007

Proteasome-dependent downregulation of activated nuclear hippocampal glucocorticoid receptors determines dynamic responses to corticosterone

Becky L. Conway-Campbell*, Mervyn A. McKenna, Crispin C. Wiles, Helen C. Atkinson, E. Ron de Kloet, and Stafford L. Lightman

Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology. Department of Medicine, University of Bristol. Whitson St, Bristol, BS13NY.; Department of Medical Pharmacology, LACDR, Leiden University Medical Center, The Netherlands

* To whom correspondence should be addressed. E-mail: b.conway-campbell{at}bristol.ac.uk.

Timing is a critical factor in neuroendocrinology. Despite this, the temporal aspects of glucocorticoid signaling in the regulation of in vivo targets has been largely overlooked. Here we present data showing that plasma glucocorticoid levels differ greatly from the constant signal predominantly utilized in cell culture experiments. Using an automated blood sampling system, we found that under basal conditions in non-stressed rats, corticosterone release occurs in discrete pulses of various amplitude dependent on the circadian cycle. This basal pattern changes to a prolonged elevated non-pulsatile release in response to stressful stimuli. We have been able to recapitulate these different patterns of corticosterone presentation (short pulse versus prolonged elevation) in adrenalectomised rats and show that each pattern results in differential activation of hippocampal glucocorticoid and mineralocorticoid receptors. Finally we provide evidence for a rapid proteasome-dependent clearance of activated glucocorticoid receptors, but not mineralocorticoid receptors, as a novel mechanism to allow dynamic interaction with rapidly changing physiological and environmental conditions.
Key words: Neuroendocrinology • pulsatility • corticosterone • glucocorticoid receptor (GR) • mineralocorticoid receptor (MR) • proteasome • MG132 • hippocampus




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