The role of FKBP5, a co-chaperone of the glucocorticoid receptor in the pathogenesis and therapy of affective and anxiety disorders

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.