The signaling pathways underlying BDNF-induced Nrf2 hippocampal nuclear translocation involve ROS, RyR-Mediated Ca2+ signals, ERK and PI3K
The signaling pathways underlying BDNF-induced Nrf2 hippocampal nuclear translocation involve ROS, RyR-Mediated Ca2+ signals, ERK and PI3K
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DOI：
10.1016/j.bbrc.2018.09.080
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发表时间：
2018-10-20
影响因子：
3.1
通讯作者：
Adasme, Tatiana
中科院分区：
文献类型：
--
作者：
Bruna, Barbara;Lobos, Pedro;Adasme, Tatiana
神经营养因子脑源性神经营养因子（BDNF）诱导复杂的神经元信号级联反应，这对突触可塑性背后的细胞变化至关重要。这些途径包括通过n -甲基- d -天冬氨酸受体激活Ca2+进入和一氧化氮合酶和NADPH氧化酶的顺序激活，通过生成活性氮/氧刺激Ca2+诱导的Ca2+释放，由Ryanodine受体（RyR）通道介导。这些连续的事件是bdnf诱导的脊柱重塑和2型RyR上调的基础。此外，BDNF诱导转录因子Nrf2的核易位，Nrf2是抗氧化蛋白表达的主要调节因子，保护细胞免受损伤和炎症引起的氧化损伤。为了研究在原代海马培养中介导Nrf2核易位的可能的bdnf诱导的信号级联反应，我们在这里测试了活性氧、ryr介导的Ca2+释放、ERK或PI3K是否有助于这种反应。我们发现，用抑制ryr介导的Ca2+释放的ryanodine与还原剂n -乙酰半胱氨酸或ERK或PI3K活性抑制剂一起预孵育的培养物，可以阻止Nrf2与BFNF孵育6小时诱导的核易位。基于这些综合结果，我们提出BDNF作为神经元抗氧化反应诱导剂的关键作用，其特征是BDNF诱导的Nfr2核易位，涉及活性氧和ryr介导的Ca2+释放之间的串扰，以及ERK和PI3K活性的参与。(C) 2018爱思唯尔公司版权所有。
The neurotrophin Brain-Derived Neurotrophic Factor (BDNF) induces complex neuronal signaling cascades that are critical for the cellular changes underlying synaptic plasticity. These pathways include activation of Ca2+ entry via N-methyl-D-aspartate receptors and sequential activation of nitric oxide synthase and NADPH oxidase, which via generation of reactive nitrogen/oxygen species stimulate Ca2+-induced Ca2+ release mediated by Ryanodine Receptor (RyR) channels. These sequential events underlie BDNF-induced spine remodeling and type-2 RyR up-regulation. In addition, BDNF induces the nuclear translocation of the transcription factor Nrf2, a master regulator of antioxidant protein expression that protects cells against the oxidative damage caused by injury and inflammation. To investigate the possible BDNF-induced signaling cascades that mediate Nrf2 nuclear translocation in primary hippocampal cultures, we tested here whether reactive oxygen species, RyR-mediated Ca2+ release, ERK or PI3K contribute to this response. We found that pre-incubation of cultures with inhibitory ryanodine to suppress RyR-mediated Ca2+ release, with the reducing agent N-acetylcysteine or with inhibitors of ERK or PI3K activity, prevented the nuclear translocation of Nrf2 induced by incubation for 6 h with BFNF. Based on these combined results, we propose that the key role played by BDNF as an inducer of neuronal antioxidant responses, characterized by BDNF-induced Nfr2 nuclear translocation, entails crosstalk between reactive oxygen species and RyR-mediated Ca2+ release, and the participation of ERK and PI3K activities. (C) 2018 Elsevier Inc. All rights reserved.