Centro de Neurociencia, Universidad de Valparaíso, Valparaíso 2360102, Chile.
J Biol Chem. 2011 Apr 15;286(15):13382-92. doi: 10.1074/jbc.M110.213785. Epub 2011 Feb 4.
Iron deficiency hinders hippocampus-dependent learning processes and impairs cognitive performance, but current knowledge on the molecular mechanisms underlying the unique role of iron in neuronal function is sparse. Here, we investigated the participation of iron on calcium signal generation and ERK1/2 stimulation induced by the glutamate agonist N-methyl-D-aspartate (NMDA), and the effects of iron addition/chelation on hippocampal basal synaptic transmission and long-term potentiation (LTP). Addition of NMDA to primary hippocampal cultures elicited persistent calcium signals that required functional NMDA receptors and were independent of calcium influx through L-type calcium channels or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors; NMDA also promoted ERK1/2 phosphorylation and nuclear translocation. Iron chelation with desferrioxamine or inhibition of ryanodine receptor (RyR)-mediated calcium release with ryanodine-reduced calcium signal duration and prevented NMDA-induced ERK1/2 activation. Iron addition to hippocampal neurons readily increased the intracellular labile iron pool and stimulated reactive oxygen species production; the antioxidant N-acetylcysteine or the hydroxyl radical trapper MCI-186 prevented these responses. Iron addition to primary hippocampal cultures kept in calcium-free medium elicited calcium signals and stimulated ERK1/2 phosphorylation; RyR inhibition abolished these effects. Iron chelation decreased basal synaptic transmission in hippocampal slices, inhibited iron-induced synaptic stimulation, and impaired sustained LTP in hippocampal CA1 neurons induced by strong stimulation. In contrast, iron addition facilitated sustained LTP induction after suboptimal tetanic stimulation. Together, these results suggest that hippocampal neurons require iron to generate RyR-mediated calcium signals after NMDA receptor stimulation, which in turn promotes ERK1/2 activation, an essential step of sustained LTP.
铁缺乏会阻碍海马依赖的学习过程并损害认知表现，但目前关于铁在神经元功能中独特作用的分子机制的知识还很匮乏。在这里，我们研究了铁在谷氨酸激动剂 N-甲基-D-天冬氨酸 (NMDA) 诱导的钙信号产生和 ERK1/2 刺激中的作用，以及铁的添加/螯合对海马基础突触传递和长时程增强 (LTP) 的影响。向原代海马培养物中添加 NMDA 会引发持续的钙信号，该信号需要功能性 NMDA 受体，并且不依赖于通过 L 型钙通道或 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体的钙内流；NMDA 还促进了 ERK1/2 的磷酸化和核转位。用去铁胺螯合铁或用钌红抑制肌质网钙释放（RyR）可减少钙信号持续时间，并阻止 NMDA 诱导的 ERK1/2 激活。向海马神经元中添加铁会迅速增加细胞内可利用铁池并刺激活性氧的产生；抗氧化剂 N-乙酰半胱氨酸或羟基自由基捕获剂 MCI-186 可防止这些反应。在无钙培养基中培养的原代海马培养物中添加铁会引发钙信号并刺激 ERK1/2 的磷酸化；RyR 抑制可消除这些作用。铁螯合会降低海马切片中的基础突触传递，抑制铁诱导的突触刺激，并损害由强刺激诱导的海马 CA1 神经元中的持续 LTP。相比之下，铁的添加会促进在次优强直刺激后持续 LTP 的诱导。总之，这些结果表明，海马神经元在 NMDA 受体刺激后需要铁来产生 RyR 介导的钙信号，这反过来又促进了 ERK1/2 的激活，这是持续 LTP 的一个必要步骤。
