Leeds Institute of Genetics, Health & Therapeutics, Faculties of Medicine and Health, University of Leeds, United Kingdom.
Antioxid Redox Signal. 2012 Sep 1;17(5):744-55. doi: 10.1089/ars.2011.4398. Epub 2012 Apr 5.
Sublethal carbon monoxide poisoning causes prolonged neurological damage involving oxidative stress. Given the central role of Ca(2+) homeostasis and its vulnerability to stress, we investigated whether CO disrupts neuronal Ca(2+) homeostasis.
Cytosolic Ca(2+) transients evoked by muscarine in SH-SY5Y cells were prolonged by CO (applied via the donor CORM-2), and capacitative Ca(2+) entry (CCE) was dramatically enhanced. Ca(2+) store mobilization by cyclopiazonic acid was similarly augmented, as was the subsequent CCE, and that evoked by thapsigargin. Ca(2+) rises evoked by depolarization were also enhanced by CO, and Ca(2+) levels often did not recover in its presence. CO increased intracellular nitric oxide (NO) and all effects of CO were prevented by inhibiting NO formation. However, NO donors did not mimic the effects of CO. The antioxidant ascorbic acid inhibited effects of CO on Ca(2+) signaling, as did the peroxynitrite scavenger, FeTPPS, and CO increased peroxynitrite formation. Finally, CO caused significant loss of plasma membrane Ca(2+)ATPase (PMCA) protein, detected by Western blot, and this was also observed in brain tissue of rats exposed to CO in vivo.
The cellular basis of CO-induced neurotoxicity is currently unknown. Our findings provide the first data to suggest signaling pathways through which CO causes neurological damage, thereby opening up potential targets for therapeutic intervention.
CO stimulates formation of NO and reactive oxygen species which, via peroxynitrite formation, inhibit Ca(2+) extrusion via PMCA, leading to disruption of Ca(2+) signaling. We propose this contributes to the neurological damage associated with CO toxicity.
亚致死性一氧化碳中毒导致氧化应激相关的长期神经损伤。鉴于钙稳态的核心作用及其对压力的脆弱性，我们研究了 CO 是否会破坏神经元钙稳态。
CO（通过供体 CORM-2 施加）延长了 SH-SY5Y 细胞中乙酰胆碱引起的细胞浆 Ca(2+) 瞬变，并且电容性 Ca(2+) 内流（CCE）显著增强。同样，环匹阿尼酸引起的 Ca(2+) 储存动员、随后的 CCE 和 thapsigargin 引起的 CCE 也被增强。CO 还增强了去极化引起的 Ca(2+) 上升，并且在其存在下 Ca(2+) 水平通常不会恢复。CO 增加了细胞内一氧化氮（NO）的产生，并且 CO 的所有作用都可以通过抑制 NO 形成来预防。然而，NO 供体不能模拟 CO 的作用。抗氧化剂抗坏血酸抑制了 CO 对 Ca(2+) 信号转导的作用，过氧亚硝酸盐清除剂 FeTPPS 也是如此，并且 CO 增加了过氧亚硝酸盐的形成。最后，CO 导致质膜 Ca(2+)ATP 酶（PMCA）蛋白的显著损失，通过 Western blot 检测到，并且在体内暴露于 CO 的大鼠脑组织中也观察到了这种情况。
目前尚不清楚 CO 诱导神经毒性的细胞基础。我们的发现提供了第一个数据，表明 CO 引起神经损伤的信号通路，从而为治疗干预开辟了潜在的靶点。
CO 刺激一氧化氮和活性氧的形成，通过过氧亚硝酸盐的形成，抑制 PMCA 介导的 Ca(2+) 外排，导致 Ca(2+) 信号转导中断。我们提出这有助于与 CO 毒性相关的神经损伤。
