title: FKBP51 inhibits GSK3β and augments the effects of distinct psychotropic medications.
abstract: Psychotropic medications target glycogen synthase kinase 3β (GSK3β), but the functional integration with other factors relevant for drug efficacy is poorly understood. We discovered that the suggested psychiatric risk factor FK506 binding protein 51 (FKBP51) increases phosphorylation of GSK3β at serine 9 (pGSK3β(S9)). FKBP51 associates with GSK3β mainly through its FK1 domain; furthermore, it also changes GSK3β's heterocomplex assembly by associating with the phosphatase PP2A and the kinase cyclin-dependent kinase 5. FKBP51 acts through GSK3β on the downstream targets Tau, β-catenin and T-cell factor/lymphoid enhancing factor (TCF/LEF). Lithium and the antidepressant (AD) paroxetine (PAR) functionally synergize with FKBP51, as revealed by reporter gene and protein association analyses. Deletion of FKBP51 blunted the PAR- or lithium-induced increase in pGSK3β(S9) in cells and mice and attenuated the behavioral effects of lithium treatment. Clinical improvement in depressive patients was predicted by baseline GSK3β pathway activity and by pGSK3β(S9) reactivity to ex vivo treatment of peripheral blood mononuclear lymphocytes with lithium or PAR. In sum, FKBP51-directed GSK3β activity contributes to the action of psychotropic medications. Components of the FKBP51-GSK3β pathway may be useful as biomarkers predicting AD response and as targets for the development of novel ADs.
authors: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
authors: N C
authors: NC
authors: Gassen
authors: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany.
authors: J
authors: J
authors: Hartmann
authors: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.|Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA.
authors: A S
authors: AS
authors: Zannas
authors: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
authors: A
authors: A
authors: Kretzschmar
authors: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
authors: J
authors: J
authors: Zschocke
authors: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
authors: G
authors: G
authors: Maccarrone
authors: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
authors: K
authors: K
authors: Hafner
authors: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
authors: A
authors: A
authors: Zellner
authors: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
authors: L K
authors: LK
authors: Kollmannsberger
authors: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany.
authors: K V
authors: KV
authors: Wagner
authors: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
authors: D
authors: D
authors: Mehta
authors: Department of Clinical Research, Max Planck Institute of Psychiatry, Munich, Germany.
authors: S
authors: S
authors: Kloiber
authors: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
authors: C W
authors: CW
authors: Turck
authors: Department of Clinical Research, Max Planck Institute of Psychiatry, Munich, Germany.
authors: S
authors: S
authors: Lucae
authors: First Department of Pediatrics, University of Athens Medical School, Athens, Greece.
authors: G P
authors: GP
authors: Chrousos
authors: Department of Clinical Research, Max Planck Institute of Psychiatry, Munich, Germany.
authors: F
authors: F
authors: Holsboer
authors: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.|Department of Psychiatry and Behavioral Sciences, Emory University, Max Planck Institute of Psychiatry, Munich, Germany.
authors: E B
authors: EB
authors: Binder
authors: Department of Clinical Research, Max Planck Institute of Psychiatry, Munich, Germany.
authors: M
authors: M
authors: Ising
authors: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany.
authors: M V
authors: MV
authors: Schmidt
authors: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
authors: T
authors: T
authors: Rein
mesh_terms: D000328:Adult; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D015415:Biomarkers / Q000097:blood; D018929:Cell Culture Techniques; D002460:Cell Line; D051360:Cyclin-Dependent Kinase 5; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D057809:HEK293 Cells; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008094:Lithium; D008297:Male; D051379:Mice; D008875:Middle Aged; D010766:Phosphorylation / Q000187:drug effects; D011619:Psychotropic Drugs / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D022021:Tacrolimus Binding Proteins / Q000235:genetics* / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism; D000099159:Tacrolimus Binding Protein 5
chemical_list: D000928:Antidepressive Agents; D015415:Biomarkers; D051360:Cyclin-Dependent Kinase 5; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D008094:Lithium; D011619:Psychotropic Drugs; D022021:Tacrolimus Binding Proteins; D051176:beta Catenin; D000099159:Tacrolimus Binding Protein 5; C000605506:GSK3B protein, human; C000605507:Gsk3b protein, mouse