Mitochondrial reactive oxygen species inactivate neuronal nicotinic acetylcholine receptors and induce long-term depression of fast nicotinic synaptic transmission
Mitochondrial reactive oxygen species inactivate neuronal nicotinic acetylcholine receptors and induce long-term depression of fast nicotinic synaptic transmission
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DOI：
10.1523/jneurosci.5130-07.2008
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发表时间：
2008-02-13
影响因子：
5.3
通讯作者：
Cooper, Ellis
中科院分区：
文献类型：
--
作者：
Campanucci, Veronica A.;Krishnaswamy, Arjun;Cooper, Ellis
神经元烟碱乙酰胆碱受体（nAChR）是参与多种认知、运动和感觉行为的配体门控离子通道，靶向于富含线粒体的区室，特别是突触后结构域和突触前末端，使这些受体暴露于氧化磷酸化产生的活性氧（ROS）。此外，在某些神经退行性疾病的进展过程中，这些受体可能暴露于ROS。由于已知ROS修饰几种膜蛋白，包括某些类型的离子通道，因此提出了细胞溶质ROS升高是否会改变nAChRs功能的问题。为了解决这个问题，我们升高培养的交感神经元中的ROS，直接通过细胞内灌注ROS的神经元，间接通过阻断线粒体电子传递链，或非侵入性的瞬时NGF去除，然后我们同时测量细胞溶质ROS水平和全细胞ACh诱发电流的变化。此外，我们升高了完整神经节中节后神经元的胞质ROS，并测量了神经诱发的EPSP的变化。我们的实验表明，轻度升高的胞质活性氧，包括短暂中断的NGF信号，诱导使用依赖性的，持久的下降ACh诱发的电流培养的交感神经元和持久的抑郁症的快速神经诱发的EPSP。我们发现，这些影响的胞质活性氧是特定的nAChRs对神经元，并不会导致下降的乙酰胆碱诱发的电流对肌肉。我们的研究结果表明，在胞浆ROS的升高以使用依赖性的方式抑制神经元nAChRs，并表明，轻度氧化应激损害神经元-神经元突触的胆碱能烟碱信号介导的机制。
Neuronal nicotinic acetylcholine receptors (nAChRs), ligand-gated ion channels implicated in a variety of cognitive, motor, and sensory behaviours, are targeted to compartments rich in mitochondria, particularly postsynaptic domains and presynaptic terminals, exposing these receptors to reactive oxygen species (ROS) generated by oxidative phosphorylation. In addition, these receptors can become exposed to ROS during the progression of certain neurodegenerative diseases. Because ROS are known to modify several membrane proteins, including some types of ion channels, it raises the question of whether elevations in cytosolic ROS alter the function of nAChRs. To address this, we elevated ROS in cultured sympathetic neurons, directly by perfusing neurons intracellularly with ROS, indirectly by blocking the mitochondrial electron transport chain, or noninvasively by transient NGF removal; we then simultaneously measured changes in cytosolic ROS levels and whole-cell ACh-evoked currents. In addition, we elevated cytosolic ROS in postganglionic neurons in intact ganglia and measured changes in nerve-evoked EPSPs. Our experiments indicate that mild elevations in cytosolic ROS, including that produced by transient interruption of NGF signaling, induce a use-dependent, long-lasting rundown of ACh-evoked currents on cultured sympathetic neurons and a long-lasting depression of fast nerve-evoked EPSPs. We show that these effects of cytosolic ROS are specific to nAChRs on neurons and do not cause rundown of ACh-evoked currents on muscle. Our results demonstrate that elevations in cytosolic ROS inactivate neuronal nAChRs in a use-dependent manner and suggest that mild oxidative stress impairs mechanisms mediated by cholinergic nicotinic signaling at neuronal-neuronal synapses.