Department of Neurobiology, Duke University Medical Center, Durham, North Carolina 27710, USA.
J Neurosci. 2012 Oct 31;32(44):15521-32. doi: 10.1523/JNEUROSCI.0755-12.2012.
Reactive oxygen species (ROS) have diverse biological consequences in the mammalian CNS, but the molecular targets mediating these pleiotropic effects are incompletely understood. Like ROS, the neurotrophin receptor, TrkB receptor tyrosine kinase, has diverse effects in the developing and mature mammalian brain. Our discovery that zinc can transactivate TrkB, together with the finding that ROS can trigger zinc release from cytosolic zinc binding proteins, led us to hypothesize that ROS can transactivate TrkB in CNS neurons by a zinc-dependent mechanism. We found that both exogenous H(2)O(2) and endogenous ROS activate TrkB signaling by a Src family kinase-dependent but brain-derived neurotrophic factor-independent mechanism in cultured rat cortical neurons. Exogenous H(2)O(2) enhances cytosolic zinc content in a metallothionein-3 (MT-3)-requiring manner. Both exogenous H(2)O(2) and endogenous ROS mediated transactivation of TrkB requires intracellular zinc and MT-3. The ROS-triggered transactivation of TrkB exerts neuroprotective effects, because inhibition of TrkB kinase activity or uncoupling Shc signaling from TrkB exacerbates neuronal cell death induced by H(2)O(2). Thus, we propose a molecular signaling event whereby ROS induce release of zinc from cytosolic MT-3, the increased cytosolic zinc transactivates TrkB, and the enhanced Shc signaling downstream from TrkB promotes prosurvival effects. We suggest that such neuroprotective effects mediated by ROS are operative in diverse acute and chronic neurological disorders.
活性氧 (ROS) 在哺乳动物中枢神经系统中具有多种生物学后果，但介导这些多效性效应的分子靶标尚不完全清楚。与 ROS 一样，神经营养因子受体 TrkB 受体酪氨酸激酶在发育中和成熟的哺乳动物脑中具有多种作用。我们发现锌可以使 TrkB 转激活，并且发现 ROS 可以触发细胞质锌结合蛋白释放锌，这使我们假设 ROS 可以通过依赖锌的机制在中枢神经系统神经元中转激活 TrkB。我们发现，外源性 H₂O₂和内源性 ROS 通过Src 家族激酶依赖性但脑源性神经营养因子独立机制在培养的大鼠皮质神经元中激活 TrkB 信号。外源性 H₂O₂以依赖金属硫蛋白-3 (MT-3) 的方式增强细胞质锌含量。外源性 H₂O₂和内源性 ROS 介导的 TrkB 转激活需要细胞内锌和 MT-3。ROS 触发的 TrkB 转激活发挥神经保护作用，因为抑制 TrkB 激酶活性或使 Shc 信号与 TrkB 解偶联会加剧 H₂O₂诱导的神经元细胞死亡。因此，我们提出了一种分子信号事件，其中 ROS 诱导细胞质 MT-3 释放锌，增加的细胞质锌转激活 TrkB，而来自 TrkB 的增强的 Shc 信号促进存活效应。我们建议，ROS 介导的这种神经保护作用在多种急性和慢性神经疾病中起作用。
