Glucocorticoid regulates TrkB protein levels via c-Cbl dependent ubiquitination: a decrease in c-Cbl mRNA in the prefrontal cortex of suicide subjects.
Glucocorticoid regulates TrkB protein levels via c-Cbl dependent ubiquitination: a decrease in c-Cbl mRNA in the prefrontal cortex of suicide subjects.
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DOI：
10.1016/j.psyneuen.2014.03.020
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发表时间：
2014-07
影响因子：
3.7
通讯作者：
Pillai, Anilkumar
中科院分区：
文献类型：
--
作者：
Pandya, Chirayu;Kutiyanawalla, Ammar;Turecki, Gustavo;Pillai, Anilkumar
脑源性神经营养因子 (BDNF) 通过其受体 TrkB 发出的信号在神经发育和可塑性中发挥着至关重要的作用。压力和糖皮质激素已被证明会改变神经元中的 TrkB 信号传导，并且据报道自杀受试者的前额叶皮质存在 TrkB 表达缺陷。糖皮质激素治疗已被证明会对神经元成熟产生有害影响。然而，神经发育过程中糖皮质激素调节 TrkB 的机制尚不清楚。在这里，我们表明，急性皮质酮暴露诱导初级皮质神经元（体外第 4 天，DIV4）中 TrkB 的翻译后上调，而蛋白酶体抑制剂可以阻断这种上调。皮质酮诱导的 TrkB 蛋白水平急性增加依赖于糖皮质激素受体 (GR)。在细胞水平上，泛素 E3 连接酶 c-Cbl 介导 TrkB 稳定和皮质酮诱导的 TrkB 水平。此外，c-Cbl 中的酪氨酸激酶结合域在皮质酮诱导的 TrkB 水平中起着关键作用。用皮质酮长期治疗神经元会导致 TrkB 和 c-Cbl 蛋白水平显着降低。急性皮质酮治疗未能引起成熟神经元 (DIV 12) 中 TrkB 和 c-Cbl 蛋白水平的任何显着变化，而慢性皮质酮暴露会降低 TrkB 水平。在体内条件下，慢性皮质酮暴露诱导小鼠额叶皮层和海马中 c-Cbl 的下调。重要的是，我们首次证明自杀受试者前额皮质中 c-Cbl mRNA 水平显着降低，表明 c-Cbl 在自杀行为的病理生理学中可能发挥作用。因此，泛素蛋白酶体介导的 TrkB 调节可能是改善 BDNF 信号传导和维持应激相关神经精神疾病神经可塑性的重要机制。
Brain derived neurotrophic factor (BDNF) signaling through its receptor TrkB plays a crucial role in neurodevelopment and plasticity. Stress and glucocorticoids have been shown to alter TrkB signaling in neurons, and defects in TrkB expression have been reported in the prefrontal cortex of suicide subjects. Glucocorticoid treatment has been shown to induce deleterious effects on the neuronal maturation. However, the mechanisms involved in the regulation of TrkB by glucocorticoid during neurodevelopment are not clear. Here we show that acute corticosterone exposure induced posttranslational upregulation of TrkB in primary cortical neurons (days in vitro 4, DIV4), which was blocked by the proteasome inhibitors. Acute corticosterone-induced increase in TrkB protein levels was dependent on glucocorticoid receptor (GR). At the cellular level, ubiquitin E3 ligase c-Cbl mediates TrkB stabilization and corticosterone-induced TrkB levels. Moreover, the tyrosine kinase binding domain in c-Cbl plays a critical role in corticosterone-induced TrkB levels. Chronic treatment of neurons with corticosterone induced significant decreases in both TrkB and c-Cbl protein levels. Acute corticosterone treatment failed to induce any significant change in TrkB and c-Cbl protein levels in mature neurons (DIV 12), where as chronic corticosterone exposure reduced TrkB levels. Under an in vivo condition, chronic corticosterone exposure induced down-regulation of c-Cbl in mouse frontal cortex and hippocampus. Importantly, we demonstrate for the first time a significant decrease in c-Cbl mRNA levels in the prefrontal cortex of suicide subjects indicating the possible role of c-Cbl in the pathophysiology of suicidal behavior. Thus, ubiquitin-proteasome-mediated TrkB regulation may be an important mechanism for improving BDNF signaling and maintaining neuroplasticity in stress-related neuropsychiatric disorders.
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DOI：
10.1073/pnas.0709102105
发表时间：
2008-03-25
影响因子：
11.1
作者：
Jeanneteau, Freddy;Garabedian, Michael J.;Chao, Moses V.
通讯作者：
Chao, Moses V.
影响因子：
3.7
作者：
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影响因子：
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作者：
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通讯作者：
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25
作者：
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通讯作者：
Alberini, Cristina M.
影响因子：
4.8
作者：
Freemantle, Erika;Mechawar, Naguib;Turecki, Gustavo
通讯作者：
Turecki, Gustavo