Mineralocorticoid receptors dampen glucocorticoid receptor sensitivity to stress via regulation of FKBP5.
Mineralocorticoid receptors dampen glucocorticoid receptor sensitivity to stress via regulation of FKBP5.
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矿化皮质激素受体通过调控FKBP5抑制糖皮质激素受体对应激的敏感性。
DOI：
10.1016/j.celrep.2021.109185
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发表时间：
2021-06-01
期刊：
影响因子：
8.8
通讯作者：
Ressler KJ
中科院分区：
文献类型：
--
作者：
Hartmann J;Bajaj T;Klengel C;Chatzinakos C;Ebert T;Dedic N;McCullough KM;Lardenoije R;Joëls M;Meijer OC;McCann KE;Dudek SM;Sarabdjitsingh RA;Daskalakis NP;Klengel T;Gassen NC;Schmidt MV;Ressler KJ
对不同动态水平的压力作出反应对哺乳动物的生存至关重要。矿皮质激素受体（MR）和糖皮质激素受体（GR）信号的破坏被认为是应激相关精神疾病中观察到的下丘脑-垂体-肾上腺（HPA）轴失调的基础。在本研究中，我们发现fk506结合蛋白51 （FKBP5）在微调海马MR:GR平衡中起关键作用。初级海马神经元的生物素化寡核苷酸免疫沉淀表明，在糖皮质激素基线活性期间，Fkbp5基因的MR结合而不是GR结合调节Fkbp5的表达。值得注意的是，FKBP5和MR在小鼠和人类的海马表达模式相似，这与GR不同。小鼠的药物抑制和区域和细胞类型特异性受体缺失进一步表明，MR缺乏会降低海马FKBP5水平，并抑制应激诱导的糖皮质激素水平的增加。总的来说，我们的研究结果表明，Fkbp5基线表达的mr依赖性变化改变了GR对糖皮质激素的敏感性，为应激稳态的机制提供了见解。Hartmann等人证明MRs调节海马FKBP5的基线表达。这种调节导致急性应激期间GR对糖皮质激素敏感性的改变。结果表明，FKBP5通过调节海马MR:GR平衡的微调，作为HPA轴活性的关键调节剂。
Responding to different dynamic levels of stress is critical for mammalian survival. Disruption of mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) signaling is proposed to underlie hypothalamic-pituitary-adrenal (HPA) axis dysregulation observed in stress-related psychiatric disorders. In this study, we show that FK506-binding protein 51 (FKBP5) plays a critical role in fine-tuning MR:GR balance in the hippocampus. Biotinylated-oligonucleotide immunoprecipitation in primary hippocampal neurons reveals that MR binding, rather than GR binding, to the Fkbp5 gene regulates FKBP5 expression during baseline activity of glucocorticoids. Notably, FKBP5 and MR exhibit similar hippocampal expression patterns in mice and humans, which are distinct from that of the GR. Pharmacological inhibition and region- and cell type-specific receptor deletion in mice further demonstrate that lack of MR decreases hippocampal Fkbp5 levels and dampens the stress-induced increase in glucocorticoid levels. Overall, our findings demonstrate that MR-dependent changes in baseline Fkbp5 expression modify GR sensitivity to glucocorticoids, providing insight into mechanisms of stress homeostasis. Hartmann et al. demonstrate that MRs regulate baseline FKBP5 expression in the hippocampus. This regulation leads to a modification of GR sensitivity to glucocorticoids during acute stress. The results suggest that FKBP5 acts as a key modulator of HPA axis activity by mediating the fine-tuning of hippocampal MR:GR balance.
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DOI：
10.1038/s41583-018-0039-7
发表时间：
2018-09
期刊：
Nature reviews. Neuroscience
影响因子：
--
作者：
Fenster RJ;Lebois LAM;Ressler KJ;Suh J
通讯作者：
Suh J
影响因子：
16.2
作者：
Fanselow, Michael S.;Dong, Hong-Wei
通讯作者：
Dong, Hong-Wei
影响因子：
120.7
作者：
Binder, Elisabeth B.;Bradley, Rebekah G.;Ressler, Kerry J.
通讯作者：
Ressler, Kerry J.
影响因子：
3.7
作者：
Binder, E. B.;Kuenzel, H. E.;Holsboer, F.
通讯作者：
Holsboer, F.
影响因子：
2.5
作者：
AHIMA, R;KROZOWSKI, Z;HARLAN, R
通讯作者：
HARLAN, R