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Targeting the FKBP51/GR/Hsp90 Complex to Identify Functionally Relevant Treatments for Depression and PTSD.
ACS Chem Biol. 2018 08 17; 13(8):2288-2299.AC

Abstract

Genetic and epigenetic alterations in FK506-binding protein 5 (FKBP5) have been associated with increased risk for psychiatric disorders, including post-traumatic stress disorder (PTSD). Some of these common variants can increase the expression of FKBP5, the gene that encodes FKBP51. Excess FKBP51 promotes hypothalamic-pituitary-adrenal (HPA) axis dysregulation through altered glucocorticoid receptor (GR) signaling. Thus, we hypothesized that GR activity could be restored by perturbing FKBP51. Here, we screened 1280 pharmacologically active compounds and identified three compounds that rescued FKBP51-mediated suppression of GR activity without directly activating GR. One of the three compounds, benztropine mesylate, disrupted the association of FKBP51 with the GR/Hsp90 complex in vitro. Moreover, we show that removal of FKBP51 from this complex by benztropine restored GR localization in ex vivo brain slices and primary neurons from mice. In conclusion, we have identified a novel disruptor of the FKBP51/GR/Hsp90 complex. Targeting this complex may be a viable approach to developing treatments for disorders related to aberrant FKBP51 expression.

Authors+Show Affiliations

Department of Molecular Medicine , University of South Florida , Tampa , Florida , United States of America. USF Health Byrd Institute , University of South Florida , Tampa , Florida , United States of America.Department of Molecular Medicine , University of South Florida , Tampa , Florida , United States of America. USF Health Byrd Institute , University of South Florida , Tampa , Florida , United States of America.Department of Molecular Medicine , University of South Florida , Tampa , Florida , United States of America. USF Health Byrd Institute , University of South Florida , Tampa , Florida , United States of America.Department of Molecular Medicine , University of South Florida , Tampa , Florida , United States of America. USF Health Byrd Institute , University of South Florida , Tampa , Florida , United States of America.Department of Chemistry , University of South Florida , Tampa , Florida , United States of America.Department of Molecular Medicine , University of South Florida , Tampa , Florida , United States of America.Department of Molecular Medicine , University of South Florida , Tampa , Florida , United States of America. USF Health Byrd Institute , University of South Florida , Tampa , Florida , United States of America.Department of Molecular Medicine , University of South Florida , Tampa , Florida , United States of America. USF Health Byrd Institute , University of South Florida , Tampa , Florida , United States of America.Department of Molecular Medicine , University of South Florida , Tampa , Florida , United States of America. USF Health Byrd Institute , University of South Florida , Tampa , Florida , United States of America.Department of Molecular Medicine , University of South Florida , Tampa , Florida , United States of America. USF Health Byrd Institute , University of South Florida , Tampa , Florida , United States of America.Department Chemie , Technische Universität München , 85748 Munich , Germany.Department of Chemistry , University of South Florida , Tampa , Florida , United States of America.Department Chemie , Technische Universität München , 85748 Munich , Germany.Department of Molecular Medicine , University of South Florida , Tampa , Florida , United States of America. Department of Chemistry , University of South Florida , Tampa , Florida , United States of America. Center for Drug Discovery and Innovation , University of South Florida , Tampa , Florida , United States of America.Department of Molecular Medicine , University of South Florida , Tampa , Florida , United States of America. USF Health Byrd Institute , University of South Florida , Tampa , Florida , United States of America.Department of Molecular Medicine , University of South Florida , Tampa , Florida , United States of America. USF Health Byrd Institute , University of South Florida , Tampa , Florida , United States of America.Department of Molecular Medicine , University of South Florida , Tampa , Florida , United States of America. USF Health Byrd Institute , University of South Florida , Tampa , Florida , United States of America.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29893552

Citation

Sabbagh, Jonathan J., et al. "Targeting the FKBP51/GR/Hsp90 Complex to Identify Functionally Relevant Treatments for Depression and PTSD." ACS Chemical Biology, vol. 13, no. 8, 2018, pp. 2288-2299.
Sabbagh JJ, Cordova RA, Zheng D, et al. Targeting the FKBP51/GR/Hsp90 Complex to Identify Functionally Relevant Treatments for Depression and PTSD. ACS Chem Biol. 2018;13(8):2288-2299.
Sabbagh, J. J., Cordova, R. A., Zheng, D., Criado-Marrero, M., Lemus, A., Li, P., Baker, J. D., Nordhues, B. A., Darling, A. L., Martinez-Licha, C., Rutz, D. A., Patel, S., Buchner, J., Leahy, J. W., Koren, J., Dickey, C. A., & Blair, L. J. (2018). Targeting the FKBP51/GR/Hsp90 Complex to Identify Functionally Relevant Treatments for Depression and PTSD. ACS Chemical Biology, 13(8), 2288-2299. https://doi.org/10.1021/acschembio.8b00454
Sabbagh JJ, et al. Targeting the FKBP51/GR/Hsp90 Complex to Identify Functionally Relevant Treatments for Depression and PTSD. ACS Chem Biol. 2018 08 17;13(8):2288-2299. PubMed PMID: 29893552.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Targeting the FKBP51/GR/Hsp90 Complex to Identify Functionally Relevant Treatments for Depression and PTSD. AU - Sabbagh,Jonathan J, AU - Cordova,Ricardo A, AU - Zheng,Dali, AU - Criado-Marrero,Marangelie, AU - Lemus,Andrea, AU - Li,Pengfei, AU - Baker,Jeremy D, AU - Nordhues,Bryce A, AU - Darling,April L, AU - Martinez-Licha,Carlos, AU - Rutz,Daniel A, AU - Patel,Shreya, AU - Buchner,Johannes, AU - Leahy,James W, AU - Koren,John,3rd AU - Dickey,Chad A, AU - Blair,Laura J, Y1 - 2018/06/19/ PY - 2018/6/13/pubmed PY - 2019/3/14/medline PY - 2018/6/13/entrez SP - 2288 EP - 2299 JF - ACS chemical biology JO - ACS Chem. Biol. VL - 13 IS - 8 N2 - Genetic and epigenetic alterations in FK506-binding protein 5 (FKBP5) have been associated with increased risk for psychiatric disorders, including post-traumatic stress disorder (PTSD). Some of these common variants can increase the expression of FKBP5, the gene that encodes FKBP51. Excess FKBP51 promotes hypothalamic-pituitary-adrenal (HPA) axis dysregulation through altered glucocorticoid receptor (GR) signaling. Thus, we hypothesized that GR activity could be restored by perturbing FKBP51. Here, we screened 1280 pharmacologically active compounds and identified three compounds that rescued FKBP51-mediated suppression of GR activity without directly activating GR. One of the three compounds, benztropine mesylate, disrupted the association of FKBP51 with the GR/Hsp90 complex in vitro. Moreover, we show that removal of FKBP51 from this complex by benztropine restored GR localization in ex vivo brain slices and primary neurons from mice. In conclusion, we have identified a novel disruptor of the FKBP51/GR/Hsp90 complex. Targeting this complex may be a viable approach to developing treatments for disorders related to aberrant FKBP51 expression. SN - 1554-8937 UR - https://www.unboundmedicine.com/medline/citation/29893552/Targeting_the_FKBP51/GR/Hsp90_Complex_to_Identify_Functionally_Relevant_Treatments_for_Depression_and_PTSD L2 - https://dx.doi.org/10.1021/acschembio.8b00454 DB - PRIME DP - Unbound Medicine ER -