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Glucocorticoid Receptors in Hippocampal Neurons that Do Not Engage Proteasomes Escape from Hormone-Dependent Down-Regulation but Maintain Transactivation Activity

Department of Pharmacology (X.W., J.L.P., D.B.D.) and Neuroscience (D.B.D.), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261

Address all correspondence and requests for reprints to: Donald B. DeFranco, Department of Pharmacology, University of Pittsburgh School of Medicine, Room E1352 BST, Pittsburgh, Pennsylvania 15261. E-mail: dod1{at}pitt.edu.

The glucocorticoid receptor (GR) protein is subjected to hormone-dependent down-regulation in most cells and tissues. This reduction in receptor levels that accompanies chronic hormone exposure serves to limit hormone responsiveness and operates at transcriptional, posttranscriptional, and posttranslational levels. The ability of glucocorticoid hormones to trigger GR down-regulation may be not universal, particularly in mature and developing neurons in which conflicting results regarding hormone control of GR protein have been reported. We find that endogenous GR is not down-regulated in the HT22 mouse hippocampal cell line and in primary hippocampal neurons derived from embryonic rats. Because GR has the capacity to be ubiquitylated in HT22 cells, receptor down-regulation must be limited by defects in either targeting of polyubiquitylated receptor to the proteasome or processing of the targeted receptor by the proteasome. Despite the lack of GR down-regulation in the HT22 cells, glucocorticoid-induced transcription from transiently transfected templates is attenuated upon prolonged hormone treatment. This termination of GR transactivation is not due to inefficient nuclear import or nuclear retention of the receptor. Furthermore, GR efficiently exports from HT22 cell nuclei in hormone-withdrawn cells, indicating that the receptor has access to both nuclear and cytoplasmic degradation pathways. Our results suggest that appropriate maturation of proteasomal degradative or targeting activities may be required, particularly in hippocampal neurons, for hormone-dependent down-regulation of GR.

NURSA Molecule Pages Link:

Nuclear Receptors:   GR

Ligands:   Dexamethasone

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