Dexamethasone-Induced Down-Regulation of Nerve Growth Factor Receptor p75NTR is Mediated by Glucocorticoid Type II Receptor in PC12 Cell Model



Shimon Lecht1, Hadar Arien-Zakay1, Rinat Tabakman2, Hao Jiang3, Donald W. Fink4, Philip Lazarovic1, *
1 Department of Pharmacology and Experimental Therapeutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Ein-Kerem POB 12065, Jerusalem 91120; Israel
2 BioLine Innovations, Jerusalem 91450, Israel
3 Department of Neurology, Henry Ford Health System, Detroit, MI 48202, USA
4 Cell Therapy Branch, Division of Cellular and Gene Therapies, Center for Biologic Evaluation and Research, FDA, Rockville, MD 20825-1448, USA


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© 2007 Lecht et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: https://creativecommons.org/licenses/by/4.0/legalcode. This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

* Address correspondence to this author at the Department of Pharmacology and Experimental Therapeutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Ein-Kerem POB 12065, Jerusalem 91120; Israel; Tel: +972-2-6758729; Fax: +972-2-6757490; E-mail: philipl@ekmd.huji.ac.il


Abstract

PC12 clones are established neuronal models to investigate mechanisms involved in the cross-talk between the neurotrophins and drugs. Chronic treatment of PC12 cells with the glucocorticoid agonist drug, dexamethasone (Dex), elicited a 50% decrease in the selective binding of 125I-NGF along with a reduction in the NGF receptor p75NTR mRNA and protein levels, suggesting a transcriptional mechanism. This down regulation of p75NTR was antagonized by the glucocorticoid type II receptor (GR-2), RU-38486 but not by the minerallocorticoid receptor, RU-28318, antagonists. This process was associated with increased autophosphorylation of the NGF receptor, TrkA. Chronic treatment of PC12 with Dex abolished the NGF-induced proliferation of the cells after 20 hours and inhibited by 45% the neurite elongation after 96 hours. RU-38486 blocked Dex-induced shift of PC12 cells from dopaminergic to noradrenergic phenotype. Dexinduced down regulation of p75NTR receptor is mediated by GR-2 and is correlated with disruption of NGF induced proliferation and differentiation. This study may prove relevant with respect to the understanding of neuronal side-effects of corticosteroids.

Keywords: PC12, NGF, dexamethasone, p75NTR, TrkA, corticosteroid type-2 receptor, down regulation.