The immunophilin FK506 binding protein 51 (FKBP51) has emerged as one of
the most intensely investigated proteins in stress-related mental disorders. It was originally
characterized as Hsp90 cochaperone and part of the receptor-chaperone heterocomplex
that governs the activity of steroid receptors. It turned out that the presence of FKBP51 in this heterocomplex leads to
diminished activity of the corticosteroid receptors. In particular, based on its inhibitory action on the glucocorticoid receptor
(GR), FKBP51 was included in a candidate gene approach to discover gene polymorphisms that might be relevant for the development
and treatment of major depression. The discovery that polymorphisms in the gene coding for FKBP51 were linked
to the treatment response of depressed patients intensified the research on the role of FKBP51 in stress-related diseases
worldwide. It has become evident that FKBP51 is not only a regulator of GR action, but also a GR target. The function of this
ultrashort intracellular feedback loop is critically important for cellular and physiological stress regulation as it does not only
calibrate the function of GR, but also the levels of FKBP51. Given the pleiotropic functions of FKBP51, its levels might be
equally important for mental disorders as GR function and hence for the development of potential FKBP51 drug targets.
Keywords: FKBP51, glucocorticoid receptor, HPA axis, mental disorders, stress.
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