Merkulov V M, Merkulova T I, Bondar N P
Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090, Russia.
Biochemistry (Mosc). 2017 Mar;82(3):351-365. doi: 10.1134/S0006297917030142.
Exposure to stress activates the hypothalamic-pituitary-adrenal axis and leads to increased levels of glucocorticoid (GC) hormones. Prolonged elevation of GC levels causes neuronal dysfunction, decreases the density of synapses, and impairs neuronal plasticity. Decreased sensitivity to glucocorticoids (glucocorticoid resistance) that develops as a result of chronic stress is one of the characteristic features of stress-induced psychopathologies. In this article, we reviewed the published data on proposed molecular mechanisms that contribute to the development of glucocorticoid resistance in brain, including changes in the expression of the glucocorticoid receptor (GR) gene, biosynthesis of GR isoforms, and GR posttranslational modifications. We also present data on alterations in the expression of the FKBP5 gene encoding the main component of cell ultra-short negative feedback loop of GC signaling regulation. Recent discoveries on stress- and GR-induced changes in epigenetic modification patterns as well as normalizing action of antidepressants are discussed. GR and FKBP5 gene polymorphisms associated with stress-induced psychopathologies are described, and their role in glucocorticoid resistance is discussed.
暴露于应激会激活下丘脑-垂体-肾上腺轴，导致糖皮质激素（GC）水平升高。GC水平的长期升高会导致神经元功能障碍，降低突触密度，并损害神经元可塑性。慢性应激导致的对糖皮质激素敏感性降低（糖皮质激素抵抗）是应激诱导的精神病理学的特征之一。在本文中，我们综述了已发表的关于导致大脑中糖皮质激素抵抗发生的分子机制的数据，包括糖皮质激素受体（GR）基因表达的变化、GR亚型的生物合成以及GR的翻译后修饰。我们还展示了关于编码GC信号调节细胞超短负反馈环主要成分的FKBP5基因表达改变的数据。讨论了应激和GR诱导的表观遗传修饰模式变化以及抗抑郁药的归一化作用的最新发现。描述了与应激诱导的精神病理学相关的GR和FKBP5基因多态性，并讨论了它们在糖皮质激素抵抗中的作用。
