Inhibition of resting potassium conductances by long-term activation of the NO/cGMP/protein kinase G pathway:: A new mechanism regulating neuronal excitability
Inhibition of resting potassium conductances by long-term activation of the NO/cGMP/protein kinase G pathway:: A new mechanism regulating neuronal excitability
复制标题
DOI：
10.1523/jneurosci.1019-07.2007
复制
发表时间：
2007-06-06
影响因子：
5.3
通讯作者：
Moreno-Lopez, Bernardo
中科院分区：
文献类型：
--
作者：
Gonzalez-Forero, David;Portillo, Federico;Moreno-Lopez, Bernardo
谷氨酸诱导的兴奋性毒性，最常见的病理机制，导致神经元死亡，可能会发生，甚至与正常水平的谷氨酸，如果它与神经元兴奋性的持续增强相一致。表达一氧化氮（NO）合酶（NOS-I）的神经元在许多人类慢性神经退行性疾病中上调，对神经退行性疾病高度敏感。我们假设，在受损神经元中，NO的慢性产生可能通过调节静息或“漏”K（+）电流来增加其内在兴奋性。在成年大鼠外周XII神经损伤诱导从头NOS-I的表达和低阈值运动单位的发病率增加，后者被阻止神经元NO/cGMP通路的慢性抑制。因此，持续的NO合成维持了受损运动神经元中增强的基础活性，其被NOS-I抑制剂缓慢地恢复（在2 - 3小时的过程中）。在切片制备，持续的，但不是急性的，激活NO/cGMP途径引起了强大的增强运动神经元兴奋性独立的突触活动。此外，NO/cGMP通路的慢性激活通过蛋白激酶G（PKG）依赖性机制完全抑制TWIK相关的酸敏感性K+（ASK）电流。最后，我们发现的证据参与了这一长期机制，在调节膜兴奋性的运动神经元，因为它们的pH敏感电流大幅减少神经损伤。这种NO/cGMP/PKG介导的ASK电导调节可能代表了一种新的病理机制，导致过度兴奋和神经元对兴奋性毒性损伤敏感。这可以解释为什么NOS-I的从头表达和/或其过表达使它们在病理条件下容易发生神经变性。
Glutamate-induced excitotoxicity, the most common pathological mechanism leading to neuronal death, may occur even with normal levels of glutamate if it coincides with a persistent enhancement of neuronal excitability. Neurons expressing nitric oxide (NO) synthase (NOS-I), which is upregulated in many human chronic neurodegenerative diseases, are highly susceptible to neurodegeneration. We hypothesized that chronic production of NO in damaged neurons may increase their intrinsic excitability via modulation of resting or "leak" K (+) currents. Peripheral XIIth nerve injury in adult rats induced de novo NOS-I expression and an increased incidence of low-threshold motor units, the latter being prevented by chronic inhibition of the neuronal NO/cGMP pathway. Accordingly, sustained synthesis of NO maintained an enhanced basal activity in injured motoneurons that was slowly reverted (over the course of 2 -3 h) by NOS-I inhibitors. In slice preparations, persistent, but not acute, activation of the NO/cGMP pathway evoked a robust augment in motoneuron excitability independent of synaptic activity. Furthermore, chronic activation of the NO/cGMP pathway fully suppressed TWIK-related acid-sensitive K+ (TASK) currents through a protein kinase G (PKG)-dependent mechanism. Finally, we found evidence for the involvement of this long-term mechanism in regulating membrane excitability of motoneurons, because their pH-sensitive currents were drastically reduced by nerve injury. This NO/cGMP/PKG-mediated modulation of TASK conductances might represent a new pathological mechanism that leads to hyperexcitability and sensitizes neurons to excitotoxic damage. It could explain why de novo expression of NOS-I and/or its overexpression makes them susceptible to neurodegeneration under pathological conditions.