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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.
