This Article Full Text Full Text (PDF) All Versions of this Article: 16/9/1987    most recent Author Manuscript (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager NURSA Molecule Pages Link Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wang, X. Articles by DeFranco, D. B. Search for Related Content PubMed PubMed Citation Articles by Wang, X. Articles by DeFranco, D. B.

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

This article has been cited by other articles:

				C. S. Barr, R. L. Dvoskin, Q. Yuan, R. H. Lipsky, M. Gupte, X. Hu, Z. Zhou, M. L. Schwandt, S. G. Lindell, M. McKee, et al. CRH Haplotype as a Factor Influencing Cerebrospinal Fluid Levels of Corticotropin-Releasing Hormone, Hypothalamic-Pituitary-Adrenal Axis Activity, Temperament, and Alcohol Consumption in Rhesus Macaques Arch Gen Psychiatry, August 1, 2008; 65(8): 934 - 944. [Abstract] [Full Text] [PDF]

				B. L. Conway-Campbell, M. A. McKenna, C. C. Wiles, H. C. Atkinson, E. R. de Kloet, and S. L. Lightman Proteasome-Dependent Down-Regulation of Activated Nuclear Hippocampal Glucocorticoid Receptors Determines Dynamic Responses to Corticosterone Endocrinology, November 1, 2007; 148(11): 5470 - 5477. [Abstract] [Full Text] [PDF]

				S. R. Pondugula, N. N. Raveendran, Z. Ergonul, Y. Deng, J. Chen, J. D. Sanneman, L. G. Palmer, and D. C. Marcus Glucocorticoid regulation of genes in the amiloride-sensitive sodium transport pathway by semicircular canal duct epithelium of neonatal rat Physiol Genomics, January 12, 2006; 24(2): 114 - 123. [Abstract] [Full Text] [PDF]

				T. Rhen and J. A. Cidlowski Antiinflammatory action of glucocorticoids--new mechanisms for old drugs. N. Engl. J. Med., October 20, 2005; 353(16): 1711 - 1723. [Full Text] [PDF]

				L. Xiao, A. Qi, and Y. Chen Cultured Embryonic Hippocampal Neurons Deficient in Glucocorticoid (GC) Receptor: A Novel Model for Studying Nongenomic Effects of GC in the Neural System Endocrinology, September 1, 2005; 146(9): 4036 - 4041. [Abstract] [Full Text] [PDF]

				X. Wang and D. B. DeFranco Alternative Effects of the Ubiquitin-Proteasome Pathway on Glucocorticoid Receptor Down-Regulation and Transactivation Are Mediated by CHIP, an E3 Ligase Mol. Endocrinol., June 1, 2005; 19(6): 1474 - 1482. [Abstract] [Full Text] [PDF]

				C. L. Smith and B. W. O'Malley Coregulator Function: A Key to Understanding Tissue Specificity of Selective Receptor Modulators Endocr. Rev., February 1, 2004; 25(1): 45 - 71. [Abstract] [Full Text] [PDF]

				E. T. Alarid, M. T. Preisler-Mashek, and N. M. Solodin Thyroid Hormone Is an Inhibitor of Estrogen-Induced Degradation of Estrogen Receptor-{alpha} Protein: Estrogen-Dependent Proteolysis Is Not Essential for Receptor Transactivation Function in the Pituitary Endocrinology, August 1, 2003; 144(8): 3469 - 3476. [Abstract] [Full Text] [PDF]

				D. Owen and S. G. Matthews Glucocorticoids and Sex-Dependent Development of Brain Glucocorticoid and Mineralocorticoid Receptors Endocrinology, July 1, 2003; 144(7): 2775 - 2784. [Abstract] [Full Text] [PDF]

				H. Jiang, F. C. Nucifora Jr, C. A. Ross, and D. B. DeFranco Cell death triggered by polyglutamine-expanded huntingtin in a neuronal cell line is associated with degradation of CREB-binding protein Hum. Mol. Genet., January 1, 2003; 12(1): 1 - 12. [Abstract] [Full Text] [PDF]