FKBP51 inhibits GSK3 beta and augments the effects of distinct psychotropic 
medications

Gassen, N. C.; Hartmann, J.; Zannas, A. S.; Kretzschmar, A.; Zschocke, J.; Maccarrone, G.; Hafner, K.; Zellner, A.; Kollmannsberger, L. K.; Wag, K. V.; Mehta, D.; Kloiber, S.; Turck, C. W.; Lucae, S.; Chrousos, G. P.; Holsboer, F.; Binder, E. B.; Ising, M.; Schmidt, M. V.; Rein, T.

doi:10.1038/mp.2015.38

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FKBP51 inhibits GSK3 beta and augments the effects of distinct psychotropic medications

MPS-Authors

/persons/resource/persons80333

Gassen, N. C.
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80354

Hartmann, J.
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons160236

Zannas, A. S.
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;
external;

/persons/resource/persons146439

Kretzschmar, A.
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80611

Zschocke, J.
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80429

Maccarrone, G.
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80351

Hafner, K.
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons160195

Zellner, A.
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons129697

Kollmannsberger, L. K.
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80438

Mehta, D.
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80401

Kloiber, S.
Dept. Clinical Research, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80561

Turck, C. W.
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80426

Lucae, S.
Dept. Clinical Research, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80372

Holsboer, F.
Dept. Clinical Research, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80272

Binder, E. B.
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;
external;

/persons/resource/persons80379

Ising, M.
Dept. Clinical Research, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80514

Schmidt, M. V.
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80489

Rein, T.
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

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Citation

Gassen, N. C., Hartmann, J., Zannas, A. S., Kretzschmar, A., Zschocke, J., Maccarrone, G., et al. (2016). FKBP51 inhibits GSK3 beta and augments the effects of distinct psychotropic medications. MOLECULAR PSYCHIATRY, 21(2), 277-289. doi:10.1038/mp.2015.38.

Cite as: https://hdl.handle.net/11858/00-001M-0000-002B-BA5B-6

Abstract

Psychotropic medications target glycogen synthase kinase 3 beta (GSK3 beta), 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 GSK3 beta at serine 9 (pGSK3 beta(S9)). FKBP51 associates with GSK3 beta mainly through its FK1 domain; furthermore, it also changes GSK3 beta's heterocomplex assembly by associating with the phosphatase PP2A and the kinase cyclin-dependent kinase 5. FKBP51 acts through GSK3 beta on the downstream targets Tau, beta-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 pGSK3 beta(S9) in cells and mice and attenuated the behavioral effects of lithium treatment. Clinical improvement in depressive patients was predicted by baseline GSK3 beta pathway activity and by pGSK3 beta(S9) reactivity to ex vivo treatment of peripheral blood mononuclear lymphocytes with lithium or PAR. In sum, FKBP51-directed GSK3 beta activity contributes to the action of psychotropic medications. Components of the FKBP51-GSK3 beta pathway may be useful as biomarkers predicting AD response and as targets for the development of novel ADs.