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FKBP51 inhibits GSK3β and augments the effects of distinct psychotropic medications

Molecular Psychiatry volume 21, pages 277–289 (2016)Cite this article

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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 (pGSK3βS9). 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 pGSK3βS9 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 pGSK3βS9 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.

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Acknowledgements

We thank Daniela Harbich and Bianca Schmid for their excellent technical support. We are indebted to James Woodgett, University of Toronto, for contributing the GSK3β KO cells. We thank Kerry Ressler (Emory University) and the Grady Trauma Projekt investigators for providing RNA data.

Author Contributions

Molecular and cellular experiments: NCG, KH. Animal experiments: JH, MVS. Kinase assay: AZ. Proteomics: GM, CWT. Protein purification: AK. Clinical sample: ASZ, SK, SL, FH, EBB, MI. Statistics: MI, NCG, JH. Design of study: NCG, TR, with important input from JZ, MVS, JH. Manuscript writing: TR, NCG. Editing: JH, MI, MVS, JZ, FH, EBB, GPC, LKK. All authors have seen the manuscript and contributed suggestions.

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Authors and Affiliations

  1. Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany,

    N C Gassen, A S Zannas, A Kretzschmar, J Zschocke, G Maccarrone, K Hafner, A Zellner, L K Kollmannsberger, D Mehta, C W Turck, E B Binder & T Rein

  2. Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany,

    J Hartmann, K V Wagner & M V Schmidt

  3. Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA,

    A S Zannas

  4. Department of Clinical Research, Max Planck Institute of Psychiatry, Munich, Germany,

    S Kloiber, S Lucae, F Holsboer & M Ising

  5. First Department of Pediatrics, University of Athens Medical School, Athens, Greece,

    G P Chrousos

  6. Department of Psychiatry and Behavioral Sciences, Emory University, Max Planck Institute of Psychiatry, Munich, Germany

    E B Binder

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  1. N C Gassen
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Gassen, N., Hartmann, J., Zannas, A. et al. FKBP51 inhibits GSK3β and augments the effects of distinct psychotropic medications. Mol Psychiatry 21, 277–289 (2016). https://doi.org/10.1038/mp.2015.38

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