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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.

journal_name

Mol Psychiatry

journal_title

Molecular psychiatry

authors

Gassen NC,Hartmann J,Zannas AS,Kretzschmar A,Zschocke J,Maccarrone G,Hafner K,Zellner A,Kollmannsberger LK,Wagner KV,Mehta D,Kloiber S,Turck CW,Lucae S,Chrousos GP,Holsboer F,Binder EB,Ising M,Schmidt MV,Rein T

doi

10.1038/mp.2015.38

subject

Has Abstract

pub_date

2016-02-01 00:00:00

pages

277-89

issue

2

eissn

1359-4184

issn

1476-5578

pii

mp201538

journal_volume

21

pub_type

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