Modulation of glucocorticoid receptor nuclear translocation in neurons by immunophilins FKBP51 and FKBP52: implications for major depressive disorder.
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.
Tatro
Erick T
ET
Department of Psychiatry, University of California at San Diego, La Jolla, CA 92093-0603, USA. etatro@ucsd.edu
Everall
Ian P
IP
Kaul
Marcus
M
Achim
Cristian L
CL
D002478:Cells, Cultured; D003865:Major Depressive Disorder / Q000235:genetics / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D005786:Gene Expression Regulation; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000502:physiology; D009474:Neurons / Q000378:metabolism*; D010913:Pituitary-Adrenal System / Q000502:physiology; D021381:Protein Transport / Q000502:physiology*; D034741:RNA, Small Interfering; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D022021:Tacrolimus Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000099159:Tacrolimus Binding Protein 5
D006854:Hydrocortisone; D034741:RNA, Small Interfering; D011965:Receptors, Glucocorticoid; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5; C403485:tacrolimus binding protein 4