Glucocorticoid Receptors (GR) in Mitochondria: The Role in Chronic Stress

线粒体中的糖皮质激素受体 (GR)：在慢性应激中的作用

• 批准号: 8158119
• 负责人: MILES A. HERKENHAM
• 金额: $ 19.78万
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8158119
• 关键词: Chronic stress; Glucocorticoid Receptor; Mitochondria; Role

Chronic stress has been shown to be associated clinically with formation of depression in patients and hormones are known to mediate certain clinical manifestations of mood disorders. Chronic restraint stress induces a morphological reorganization of neurons in certain areas of rodent brain, effects that are also accompanied by behavioral changes. Although the precise mechanisms underlying these effects remain to be elucidated, a growing body of data suggests that alterations in neuroprotection and mitochondrial functions of glucocorticoid receptors may play an important role in regulating various forms of synaptic and neuronal plasticity; we have sought to investigate the mitochondrial functions regulated by steroid hormones during chronic stress. Glucocorticoids play an important biphasic role in modulating synaptic and neural events, with low doses enhancing synaptic and neuronal plasticity and chronic, higher doses producing inhibition. We undertook a series of experiments to elucidate the mechanisms underlying these biphasic effects. We found that 1) glucocorticoid receptors (GRs) formed a complex with the anti-apoptotic protein Bcl-2 in response to corticosterone treatment, and 2) translocated with Bcl-2 into mitochondria after acute treatment with low or high doses of corticosterone in primary cortical neurons. However, after three days of treatment, high but not low doses of corticosterone resulted in a decrease in GR and Bcl-2 levels in mitochondria. In addition, three independent measures of mitochondrial function, mitochondrial calcium holding capacity, mitochondrial oxidation, and membrane potential were also regulated by long-term corticosterone treatment in an inverted U-shape. This regulation of mitochondrial function by corticosterone correlated with neuroprotection: that is, treatment with low doses of corticosterone demonstrated a neuroprotective effect, whereas treatment with high doses enhanced kainic acid (KA, a neural toxin)-induced toxicity of cortical neurons. As with the in vitro studies, Bcl-2 levels in the mitochondria of the prefrontal cortex were significantly decreased, along with GR levels, after long-term treatment with high-dose corticosterone. These findings have the potential to contribute to a more complete understanding of the mechanisms by which glucocorticoids and chronic stress regulate cellular plasticity and resilience, and to inform the future development of improved therapeutic treatments. Recent studies focused on the molecular mechanism of the GR/Bcl-2 trafficking. BAG-1, a downstream target of lithium and valproate, interacts with PTSD- and depression-associated gene FKBP51, glucocorticoid receptors (GRs), Bcl-2, heat shock protein 70, and inhibits GR receptor nuclear translocation in response to corticosterone (CORT). We studied BAG-1 and FKBP51 levels in the mitochondria after CORT treatment. We found that BAG1 and FKBP51 distribution in the mitochondria was significantly increased in response to CORT treatment in cultured cortical neurons; interestingly, similar effects were seen with GR and Bcl-2 mitochondrial levels after CORT. Furthermore, FKBP51 formed a complex with BAG-1, and the formation of FKBP51 and BAG-1complex increased after CORT treatment. However, total BAG-1 protein expression was decreased in neuronal homogenates, suggesting a complex regulation by CORT. Notably, BAG-1 overexpression in BAG-1 transgenic mice not only blocked the reduction of GR/Bcl-2 in the mitochondria, but also the formation of anhedonic-like behavior after CORT treatment. Wild type FVB mice showed a reduction in saccharine consumption after CORT treatment; however, BAG-1 transgenic mice did not, suggesting a resilience to high dose CORT. These data suggest that the regulation of the trafficking of key plasticity molecules to the mitochondria may play an important role in the mechanisms by which chronic stress and glucocorticoids regulate cellular plasticity and resilience, and ultimately sensitivity/resilience to the development of stress-induced psychiatric disorders.

慢性压力在临床上与患者抑郁症的形成有关，并且已知激素介导情绪障碍的某些临床表现。慢性束缚应激诱导啮齿动物大脑某些区域神经元的形态重组，这种效应也伴随着行为变化。虽然这些影响的确切机制仍有待阐明，越来越多的数据表明，糖皮质激素受体的神经保护和线粒体功能的改变可能在调节各种形式的突触和神经元可塑性中发挥重要作用;我们试图研究慢性应激期间类固醇激素调节的线粒体功能。 糖皮质激素在调节突触和神经事件中起重要的双相作用，低剂量增强突触和神经元可塑性，而慢性高剂量产生抑制作用。我们进行了一系列的实验来阐明这些双相效应的机制。我们发现：1）皮质酮处理后，糖皮质激素受体（GR）与抗凋亡蛋白Bcl-2形成复合物，2）在低或高剂量皮质酮急性处理后，原代皮质神经元中Bcl-2易位到线粒体中。然而，治疗三天后，高剂量而不是低剂量的皮质酮导致线粒体中GR和Bcl-2水平下降。此外，三个独立的线粒体功能，线粒体钙容量，线粒体氧化和膜电位的措施也受到长期皮质酮治疗的倒U形。皮质酮对线粒体功能的调节与神经保护作用相关：即，低剂量皮质酮的治疗表现出神经保护作用，而高剂量红藻氨酸（KA，一种神经毒素）诱导的皮质神经元毒性增强。与体外研究一样，在高剂量皮质酮长期治疗后，前额叶皮质线粒体中的Bcl-2水平显著降低，沿着GR水平。这些发现有可能有助于更全面地了解糖皮质激素和慢性应激调节细胞可塑性和弹性的机制，并为未来改进治疗方法的发展提供信息。 近年来的研究主要集中在GR/Bcl-2转运的分子机制上。BAG-1是锂和丙戊酸盐的下游靶点，与PTSD和抑郁相关基因FKBP 51、糖皮质激素受体（GR）、Bcl-2、热休克蛋白70相互作用，并抑制GR受体核转位以响应皮质酮（CORT）。我们研究了CORT处理后线粒体中BAG-1和FKBP 51的水平。我们发现，BAG 1和FKBP 51在线粒体中的分布显着增加，响应CORT处理在培养的皮层神经元;有趣的是，类似的影响，观察到与GR和Bcl-2线粒体水平CORT后。 FKBP 51与BAG-1形成复合物，CORT处理后FKBP 51与BAG-1复合物的形成增加。然而，总BAG-1蛋白表达减少神经元匀浆，表明一个复杂的调节CORT。 值得注意的是，在BAG-1转基因小鼠中BAG-1过表达不仅阻止了线粒体中GR/Bcl-2的减少，而且还阻止了CORT处理后快感缺失样行为的形成。野生型FVB小鼠在CORT处理后显示糖精消耗减少;然而，BAG-1转基因小鼠没有，表明对高剂量CORT的适应性。这些数据表明，调节关键可塑性分子向线粒体的运输可能在慢性应激和糖皮质激素调节细胞可塑性和弹性的机制中发挥重要作用，并最终调节对应激诱导的精神疾病发展的敏感性/弹性。