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.
ACS Chem Biol. 2018 Aug 17;13(8):2288-2299. doi: 10.1021/acschembio.8b00454. Epub 2018 Jun 19.
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.
FK506 结合蛋白 5（FKBP5）的遗传和表观遗传改变与精神疾病的风险增加有关，包括创伤后应激障碍（PTSD）。这些常见的变体中的一些可以增加 FKBP5 的表达，FKBP5 基因编码 FKBP51。过多的 FKBP51 通过改变糖皮质激素受体（GR）信号传导促进下丘脑-垂体-肾上腺（HPA）轴失调。因此，我们假设通过扰乱 FKBP51 可以恢复 GR 活性。在这里，我们筛选了 1280 种具有药理活性的化合物，并鉴定出三种可以恢复 FKBP51 介导的 GR 活性抑制而不直接激活 GR 的化合物。这三种化合物之一，苯扎托品甲磺酸盐，在体外破坏 FKBP51 与 GR/Hsp90 复合物的结合。此外，我们表明，苯扎托品通过从该复合物中去除 FKBP51 来恢复 GR 在离体脑切片和来自小鼠的原代神经元中的定位。总之，我们已经确定了 FKBP51/GR/Hsp90 复合物的一种新型破坏剂。靶向该复合物可能是开发与异常 FKBP51 表达相关的疾病治疗方法的可行方法。
