Evaluation of the role of nitric oxide in acid sensing ion channel mediated cell death
Evaluation of the role of nitric oxide in acid sensing ion channel mediated cell death
复制标题
DOI：
10.1016/j.niox.2009.12.006
复制
发表时间：
2010-04-01
影响因子：
3.9
通讯作者：
Bera, Amal Kanti
中科院分区：
文献类型：
--
作者：
Jetti, Suresh Kumar;Swain, Sandip Madhusudan;Bera, Amal Kanti
酸敏感离子通道（acidsensingionchannels，ASICs）广泛表达于中枢和外周神经系统.它们参与多种生理和病理生理过程：突触传递、学习和记忆、疼痛感知、缺血等。在缺血期间，代谢性酸中毒导致细胞外pH（pHe）下降，这反过来激活ASIC。钙渗透性ASIC 1a的激活与神经元死亡有关。ASIC由几种氧化还原试剂、二价阳离子和一氧化氮（NO）调节。虽然NO增强ASIC介导的电流，但这种调制的生理意义尚未详细研究。我们已经评估了内源性NO在不同pH值下由ASIC激活介导的细胞死亡中的作用。在pH 6.1下，与不表达ASIC的细胞相比，表达ASIC 1的Neuro 2A（N2 A）细胞的死亡率显著更高。阿米洛利，ASICs的阻断剂，保护细胞免受酸损伤。硝普钠是一种有效的NO供体，不仅增加ASIC介导的电流，而且在低pH下增加细胞死亡。NO前体L-Arg也以pH依赖性方式增强ASIC。在pH7.4、7.2、7.0和6.8下观察到L-Arg诱导的NO产生和增强ASIC。将pH降低至6.8以下不会导致NO的显著产生或L-Arg刺激后ASIC的增强。我们的研究结果表明，增强ASIC的NO和随后的细胞死亡在体内取决于酸中毒的严重程度。在轻度和中度酸中毒期间，NO通过增强ASIC促进细胞死亡，而这种增强作用在严重酸中毒中由于NO合酶的抑制而消退。(C)2010年爱思唯尔公司All rights reserved.
Acid sensing ion channels (ASICs) are widely expressed in central and peripheral nervous system. They are involved in a variety of physiological and pathophysiological processes: synaptic transmission, learning and memory, pain perception, ischemia, etc. During ischemia, metabolic acidosis causes the drop of extracellular pH (pHe) which in turn activates ASICs. Activation of calcium permeable ASIC1a has been implicated in neuronal death. ASICs are modulated by several redox reagents, divalent cations and nitric oxide (NO). Although NO potentiates ASIC mediated currents, the physiological significance of such modulation has not been studied in detail. We have evaluated the role of endogenous NO in cell death at different pH, mediated by the activation of ASICs. At pH 6.1, death rates of ASIC1 expressing Neuro2A (N2A) cells are significantly higher in comparison to the cells that do not express ASICs. Amiloride, a blocker of ASICs protects the cell from acid-injury. Sodium nitroprusside, a potent NO donor not only increases the ASIC mediated currents but also increases cell death at low pH. L-Arg, the precursor of NO also potentiates ASICs in a pH dependent manner. L-Arg-induced NO production and potentiation of ASICs were observed at pHs 7.4, 7.2, 7.0 and 6.8. Lowering the pH below 6.8 did not result in significant production of NO or potentiation of ASICs upon L-Arg stimulation. Our results suggest that potentiation of ASICs by NO and subsequent cell death in vivo depends on the severity of acidosis. During mild and moderate acidosis, NO promotes cell death by potentiating ASICs, whereas this potentiation subsides in severe acidosis due to inhibition of NO synthase. (C) 2010 Elsevier Inc. All rights reserved.