Glucocorticoid resistance in squirrel monkeys results from a combination of overexpression of the glucocorticoid receptor cochaperone FKBP51 and mutations in the receptor

Abstract

Squirrel monkeys (SM) and other New World primates have elevated circulating cortisol to compensate for end organ insensitivity to glucocorticoids (GC). Several laboratories have investigated the cause of GC resistance in SM, but these studies have provided different explanations. It has been suggested that either high levels of FKBP51 (that lead to reduced binding affinity) or naturally occurring mutations in the glucocorticoid receptor (GR) (that reduce transactivation efficiency) are responsible for GC resistance. Here, we sought to reach a consensus on the contribution of each mechanism. First, we generated dexamethasone (DEX)-response curves in COS-7 cells transfected with either human or SM GR. Although the maximum response to DEX was not different, we confirmed earlier observations that revealed a 34-fold higher EC50 for sm GR, suggesting that it is inherently less active. We next tested whether expression of FKBP51 in COS-7 and 293 cells has an additional inhibitory effect on sm GR activity. We found that expression of FKBP51 had a similar inhibitory effect on SM GR and human GR, shifting both EC50s for DEX to the right. The EC50 for DEX in cells expressing SM GR and FKBP51 was 15 nM, compared to the EC50 in cells expressing only human GR (0.14 nM). These results are consistent with the 50–100 fold higher cortisol found in this species, suggesting that expression of FKBP51 and GR mutations likely contribute to GC resistance in squirrel monkeys. Supported by grants 13200 and 01254 from NCRR.