The lipid peroxidation product 4-hydroxynonenal facilitates opening of voltage-dependent Ca2+Channels in neurons by increasing protein tyrosine phosphorylation
The lipid peroxidation product 4-hydroxynonenal facilitates opening of voltage-dependent Ca2+Channels in neurons by increasing protein tyrosine phosphorylation
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DOI：
10.1074/jbc.m201924200
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发表时间：
2002-07-05
影响因子：
4.8
通讯作者：
Mattson, MP
中科院分区：
文献类型：
--
作者：
Lu, CB;Chan, SL;Mattson, MP
通过电压依赖性钙通道（VDCC）的钙内流介导神经元和其他可兴奋细胞中的多种功能，但是通过这些通道的过量钙内流可导致病理环境中的神经元死亡。在神经元回路的正常活动中，神经元中发生氧自由基产生和膜脂质过氧化，而过度的脂质过氧化与神经退行性疾病的发病机制有关。我们现在报告一个特定的机制，脂质过氧化可以调节VDCCs的活动。脂质过氧化产物4-羟基-2，3-壬烯醛（4 HN）增强二氢吡啶敏感的全细胞Ca 2+电流，并增加去极化诱导的海马神经元细胞内Ca 2+水平的增加。长时间暴露于4 HN导致神经元死亡，这通过用谷胱甘肽治疗来防止，并通过L型Ca 2+通道阻断剂尼莫地平来减弱。在暴露于4 HN的神经元中，α 1 VDCC亚基的酪氨酸磷酸化增加，并且使用酪氨酸激酶和磷酸酶抑制剂的研究表明，在响应于4 HN的VDCC活性增强中需要酪氨酸磷酸化。磷酸化介导的钙离子通道活性的调节在脂质过氧化反应中可能在神经元对氧化应激的生理和病理反应中发挥重要作用。
Calcium influx through voltage-dependent calcium channels (VDCCs) mediates a variety of functions in neurons and other excitable cells, but excessive calcium influx through these channels can contribute to neuronal death in pathological settings. Oxyradical production and membrane lipid peroxidation occur in neurons in response to normal activity in neuronal circuits, whereas excessive lipid peroxidation is implicated in the pathogenesis of of neurodegenerative disorders. We now report on a specific mechanism whereby lipid peroxidation can modulate the activity of VDCCs. The lipid peroxidation product 4-hydroxy-2,3-nonenal (4HN) enhances dihydropyridine-sensitive whole-cell Ca2+ currents and increases depolarization-induced increases of intracellular Ca2+ levels in hippocampal neurons. Prolonged exposure to 4HN results in neuronal death which is prevented by treatment with glutathione an attenuated by the L-type Ca2+ channel blocker nimodipine. Tyrosine phosphorylation of alpha1 VDCC subunits is increased in neurons exposed to 4HN, and studies using inhibitors of tyrosine kinases and phosphatases indicate a requirement for tyrosine phosphorylation in the enhancement of VDCC activity in response to 4HN. Phosphorylation-mediated modulation of Ca2+ channel activity in response to lipid peroxidation may play important roles in the responses of neurons to oxidative stress in both physiological and pathological settings.