FKBP4 and FKBP5 (over 2-fold higher) and NR3C1 itself are downstream targets of glucocorticoid signaling. FKBP5 functions as a negative regulator of the pathway by lowering the cortisol affinity of the glucocorticoid receptor and keeping it in the cytoplasm, which increases cortisol resistance and short-circuits the glucocorticoid feedback circuit (Binder, 2009; Binder et al., 2008). Mice with chronic exposure to corticosterone (the rodent equivalent of cortisol) develop anxiety and have decreased expression of Nr3c1 and Hsp90 and increased expression of FKBP5 in many tissues (Lee et al., 2010). Increased FKBP5 expression due to known polymorphisms leads to increased risk of affective and anxiety disorders (Binder et al., 2008) and bipolar disorder (Willour et al., 2009).
