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The glucocorticoid receptor–FKBP51 complex contributes to fear conditioning and posttraumatic stress disorder
Haiyin Li, … , Kerry J. Ressler, Fang Liu
Haiyin Li, … , Kerry J. Ressler, Fang Liu
Published January 13, 2020
Citation Information: J Clin Invest. 2020;130(2):877-889. https://doi.org/10.1172/JCI130363.
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Research Article Neuroscience

The glucocorticoid receptor–FKBP51 complex contributes to fear conditioning and posttraumatic stress disorder

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Abstract

Posttraumatic stress disorder (PTSD) can develop after exposure to severe psychological trauma, leaving patients with disabling anxiety, nightmares, and flashbacks. Current treatments are only partially effective, and development of better treatments is hampered by limited knowledge of molecular mechanisms underlying PTSD. We have discovered that the glucocorticoid receptor (GR) and FK506 binding protein 51 (FKBP51) form a protein complex that is elevated in PTSD patients compared with unaffected control subjects, subjects exposed to trauma without PTSD, and patients with major depressive disorder (MDD). The GR-FKBP51 complex is also elevated in fear-conditioned mice, an aversive learning paradigm that models some aspects of PTSD. Both PTSD patients and fear-conditioned mice had decreased GR phosphorylation, decreased nuclear GR, and lower expression of 14-3-3ε, a gene regulated by GR. We created a peptide that disrupts GR-FKBP51 binding and reverses behavioral and molecular changes induced by fear conditioning. This peptide reduces freezing time and increases GR phosphorylation, GR-FKBP52 binding, GR nuclear translocation, and 14-3-3ε expression in fear-conditioned mice. These experiments demonstrate a molecular mechanism contributing to PTSD and suggest that the GR-FKBP51 complex may be a diagnostic biomarker and a potential therapeutic target for preventing or treating PTSD.

Authors

Haiyin Li, Ping Su, Terence K.Y. Lai, Anlong Jiang, Jing Liu, Dongxu Zhai, Charlie T.G. Campbell, Frankie H.F. Lee, WeiDong Yong, Suvercha Pasricha, Shupeng Li, Albert H.C. Wong, Kerry J. Ressler, Fang Liu

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Figure 6

Summary of the molecular pathways within the neuron in the presence of TAT-GRpep.

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Summary of the molecular pathways within the neuron in the presence of T...
(A) TAT-GRpep is able to pass through the blood brain barrier and enter into the neuron due to the TAT sequence. (B) Once TAT-GRpep enters the cell, it competes with GR in binding to FKBP51. (C) More GR is phosphorylated and (D) consequently, more GR can bind to FKBP52. (E) Both events are responsible for translocating GR into the nucleus, where it binds to specific DNA sequences and promotes transcription.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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