Modulation of glucocorticoid receptor nuclear translocation in neurons by immunophilins FKBP51 and FKBP52: Implications for major depressive disorder

• Published in: Brain research Vol. 1286; pp. 1 - 12
• Main Authors: Tatro, Erick T, Everall, Ian P, Kaul, Marcus, Achim, Cristian L
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 25.08.2009; Elsevier
• Subjects: Adult and adolescent clinical studies; Biological and medical sciences; Cells, Cultured; Depression; Depressive Disorder, Major - genetics; Depressive Disorder, Major - metabolism; FK506-binding proteins; FKBP51; FKBP52; Fluorescent Antibody Technique; Gene Expression; Gene Expression Regulation; Glucocorticoid receptor; Humans; Hydrocortisone - metabolism; Hypothalamo-Hypophyseal System - physiology; Immunophilins; Medical sciences; Mood disorders; Neurology; Neurons - metabolism; Nuclear translocation; Pituitary-Adrenal System - physiology; Protein Transport - physiology; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Receptors, Glucocorticoid - metabolism; RNA, Small Interfering; Tacrolimus Binding Proteins - genetics; Tacrolimus Binding Proteins - metabolism; Immunophilins; glucocorticoid receptor; FK506 Binding Protein of 51 kDa; FKBP52; Nuclear translocation; hypothalamic–pituitary–adrenal; HPA; FK506 Binding Protein of 52 kDa; GR; FK506-binding proteins; FKBP51; Glucocorticoid receptor; Mood disorder; Human; Nuclear receptor; Central nervous system; Depression; In vitro; Encephalon; Binding protein; Neuron; Tacrolimus
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2009.06.036

Abstract Mood disorders associated with dysfunction of the hypothalamic–pituitary–adrenal (HPA) axis are common psychiatric conditions. The glucocorticoid receptor (GR) is a steroid-activated nuclear receptor that, upon binding to cortisol, translocates to the nucleus where it targets genes related to neuronal metabolism and plasticity. In patients suffering from major depressive disorder (MDD), hypercortisolemia is a common finding. In the current study we investigated the molecular events associated with the FK506 binding proteins (FKBP) -52 and -51 response to cortisol exposure in neuronal cell cultures and their effect on GR translocation. We noted that FK506 altered nuclear localization of the GR and inhibited expression of GR-responsive genes. Furthermore, siRNA knockdown of FKBP4 gene, coding for the immunophilin FKBP52, inhibited cortisol-activated GR nuclear translocation, while knockdown of FKBP5 , coding for immunophilin FKBP51, was associated with increased baseline GR nuclear localization. We propose that immunophilins are modulators of the cortisol–HPA axis response to stress and related chronic brain disorders.