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Proteasome-Dependent Down-Regulation of Activated Nuclear Hippocampal Glucocorticoid Receptors Determines Dynamic Responses to Corticosterone

Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology (B.L.C.-C., M.A.M., C.C.W., H.C.A., S.L.L.), Department of Medicine, University of Bristol, Bristol BS1 3NY, United Kingdom; and Department of Medical Pharmacology (E.R.d.K.), Leiden/Amsterdam Center for Drug Research, Leiden University Medical Center, 2300 RA Leiden, The Netherlands

Address all correspondence and requests for reprints to: Becky L. Conway-Campbell, Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, Dorothy Hodgkins Building, University of Bristol, Whitson Street, Bristol BS1 3NY, United Kingdom. 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 have been largely overlooked. Here, we present data showing that plasma glucocorticoid levels differ greatly from the constant signal predominantly used in cell culture experiments. Using an automated blood sampling system, we found that under basal conditions in nonstressed rats, corticosterone release occurs in discrete pulses of various amplitudes dependent on the circadian cycle. This basal pattern changes to a prolonged elevated nonpulsatile release in response to stressful stimuli. We have been able to recapitulate these different patterns of corticosterone presentation (short pulse vs. prolonged elevation) in adrenalectomized 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.

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