Differential mechanisms underlying the modulation of delayed-rectifier K+ channel in mouse neocortical neurons by nitric oxide
Differential mechanisms underlying the modulation of delayed-rectifier K+ channel in mouse neocortical neurons by nitric oxide
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DOI：
10.1152/jn.01185.2004
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发表时间：
2006-04-01
影响因子：
2.5
通讯作者：
Sheu, FS
中科院分区：
文献类型：
--
作者：
Han, NLR;Ye, JS;Sheu, FS
一氧化氮（NO）对电压依赖性钾通道的调节作用是复杂的。本研究采用全细胞膜片钳和细胞贴附式膜片钳技术，观察了NO供体S-硝基-N-乙酰青霉胺（SNAP）和溶解态NO对小鼠新皮层神经元K+电流的增强和抑制作用。通过使用特定的电化学传感器，NO的增加或减少通道活动的临界浓度被准确定量。低浓度SNAP（20 μ M）或NO溶液（0.1 μ M）可增强全细胞延迟整流钾电流（I-K），而使快速失活A电流（I-A）保持不变。然而，高浓度的SNAP（100 μ M）和NO（0.5 μ M）降低I-K和I-A电流。在细胞贴壁实验中，当使用低浓度的SNAP或NO时，观察到通道开放概率（NP 0）显著增加。高浓度的SNAP或NO显著降低NP 0。通道活动的增加，低浓度的SNAP被取消的存在下，无论是抑制剂的可溶性胍基酸环化酶或cGMP依赖性蛋白激酶G的抑制剂，这表明一个链接到NO-cGMP信号级联。高浓度的SNAP的通道活动的减少被逆转的还原剂二硫苏糖醇，这意味着氧化还原反应机制。因此，NO-cGMP信号传导和氧化还原机制都参与调节神经元兴奋性的I-K通道活性。
The modulatory effects of nitric oxide (NO) on voltage-dependent K+ channels are intricate. In our present study, the augmentation and reduction of K+ currents by NO donor S-nitro-N-acetylpenicillamine ( SNAP) and pure dissolved NO was observed in dissociated neurons from mice neocortex with both whole cell and cell-attached patch clamp. By using a specific electrochemical sensor, the critical concentrations of NO that increased or reduced the channel activities were accurately quantified. Low concentrations of SNAP ( 20 mu M) or NO solution ( 0.1 mu M) enhanced whole cell delayed rectifier K+-current (I-K) and left the fast inactivating A current (I-A) unchanged. However, high concentrations of SNAP ( 100 mu M) and NO ( 0.5 mu M) reduced both I-K and I-A currents. In cell-attached experiments, a significant increase in channel open probability (NP0) was observed when using low concentrations of SNAP or NO. High concentrations of SNAP or NO dramatically decreased NP0. The increase in channel activities by low concentrations of SNAP was abolished in the presence of either inhibitors of soluble guaylate cyclase or inhibitors of cGMP-dependent protein kinase G, suggesting a link to the NO-cGMP signaling cascade. The reduction of channel activities by high concentrations of SNAP was reversed by the reducing agent dithiothreitol, implying a redox reaction mechanism. Thus both NO-cGMP signaling and a redox mechanism are involved in the modulation of I-K channel activity for neuron excitability.