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Published on: September 10, 2013
The animal and cell models that uncovered FKBP51 as a regulator of glucocorticoid receptor function
1Departments of Comparative Medicine and Pharmacology, Frederick P. Whiddon College of Medicine, University of South Alabama, Mobile, Alabama, USA.
Abstract:
Many New World primates are glucocorticoid-resistant secondary to expression of low affinity glucocorticoid receptors. We identified the role of FKBP51 in hormone responsiveness by showing that multiple cell lines derived from New World primates share the same activities: (1) soluble cell extracts conferred low binding affinity to high affinity glucocorticoid receptors; (2) FK506 increased receptor binding in soluble cell extracts; and (3) cellular FKBP51 was elevated and FKBP52 was lower. Details of these cell lines and their availability are described. Subsequently, we showed that New World primate and human FKBP51 decreased glucocorticoid activity in heterologous COS-7 cell cultures. Future studies using the FKBP51 antagonist SAFit2 in New World primates are proposed.
Insights
New World primates exhibit glucocorticoid resistance due to low-affinity receptors. FKBP51 elevation contributes to this resistance, impacting hormone responsiveness and offering potential therapeutic targets.
Area of Science:
- Endocrinology
- Primate Biology
- Molecular Biology
Background:
- New World primates often display resistance to glucocorticoids.
- This resistance is linked to the expression of low-affinity glucocorticoid receptors.
- The molecular mechanisms underlying this phenomenon require further elucidation.
Purpose of the Study:
- To investigate the role of FKBP51 in mediating glucocorticoid receptor affinity and hormone responsiveness in New World primates.
- To characterize cellular changes associated with glucocorticoid resistance in primate cell lines.
- To explore the potential of FKBP51 modulation as a therapeutic strategy.
Main Methods:
- Analysis of soluble cell extracts from New World primate cell lines to assess glucocorticoid receptor binding affinity.
- Treatment with FK506 to observe effects on receptor binding.
- Quantification of FKBP51 and FKBP52 protein levels in cellular extracts.
- Heterologous expression studies in COS-7 cells using primate and human FKBP51 to evaluate effects on glucocorticoid activity.
Main Results:
- Soluble cell extracts from New World primate cell lines demonstrated low binding affinity for glucocorticoid receptors.
- FK506 treatment increased receptor binding in these extracts.
- Elevated cellular FKBP51 and reduced FKBP52 levels were observed in the studied cell lines.
- Both New World primate and human FKBP51 were found to decrease glucocorticoid activity in heterologous COS-7 cell cultures.
Conclusions:
- FKBP51 plays a significant role in the glucocorticoid resistance observed in New World primates.
- The modulation of FKBP51 levels impacts glucocorticoid receptor affinity and cellular hormone responsiveness.
- Further research utilizing FKBP51 antagonists, such as SAFit2, is warranted for therapeutic applications in New World primates.
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