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Abstract
FK506 binding protein 51 or FKBP5 is a co-chaperone of hsp90 which regulates glucocorticoid
receptor (GR) sensitivity. When it is bound to the receptor complex, cortisol binds
with lower affinity and nuclear translocation of the receptor is less efficient. FKBP5
mRNA and protein expression are induced by GR activation via intronic hormone response
elements and this provides an ultra-short feedback loop for GR-sensitivity. Polymorphisms
in the gene encoding this co-chaperone have been shown to associate with differential
upregulation of FKBP5 following GR activation and differences in GR sensitivity and
stress hormone system regulation. Alleles associated with enhanced expression of FKBP5
following GR activation, lead to an increased GR resistance and decreased efficiency
of the negative feedback of the stress hormone axis in healthy controls. This results
in a prolongation of stress hormone system activation following exposure to stress.
This dysregulated stress response might be a risk factor for stress-related psychiatric
disorders. In fact, the same alleles are over-represented in individuals with major
depression, bipolar disorder and post-traumatic stress disorder. In addition, they
are also associated with faster response to antidepressant treatment. FKBP5 might
thus be an interesting therapeutic target for the prevention and treatment of stress-related
psychiatric disorders.