Mitochondrial reactive oxygen species are activated by mGluR5 through IP3 and activate ERK and PKA to increase excitability of amygdala neurons and pain behavior.
Mitochondrial reactive oxygen species are activated by mGluR5 through IP3 and activate ERK and PKA to increase excitability of amygdala neurons and pain behavior.
复制标题
线粒体活性氧通过 IP3 被 mGluR5 激活，并激活 ERK 和 PKA，从而增加杏仁核神经元的兴奋性和疼痛行为。
DOI：
10.1523/jneurosci.5387-10.2011
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发表时间：
2011-01-19
期刊：
影响因子：
--
通讯作者：
Neugebauer V
中科院分区：
文献类型：
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作者：
Li Z;Ji G;Neugebauer V
活性氧簇(ROS)，如超氧化物歧化，正在成为重要的信号分子在生理可塑性，但也在周围和脊髓疼痛病理。大脑中潜在的机制和与疼痛相关的ROS信号仍有待确定。杏仁核的神经可塑性在情绪性疼痛反应中起关键作用，并依赖于I组代谢性谷氨酸受体(MGluRs)和蛋白激酶。使用膜片钳、活细胞成像和行为分析，我们检验了线粒体ROS将I组mGluRs与蛋白激酶激活联系起来以增加神经元的兴奋性和疼痛行为的假设。MGluR1/5激动剂(DHPG)或mGluR5激动剂(CHPG)可增加杏仁中央核(CeLC)囊外侧区神经元的兴奋性。MGluR5拮抗剂(MTEP)、IP3受体阻断剂(Xestospongin C)或ROS清除剂(PBN、tempoll)可抑制DHPG的作用，而mGluR5拮抗剂(LY367385)和一氧化氮合酶抑制剂(L-NAME)不能抑制DHPG的作用。Tempol可抑制IP3的作用，但不能抑制PKC激活剂的作用，表明ROS的激活是IP3介导的。含CeLC的脑片的活细胞成像直接显示了DHPG诱导和突触诱发的线粒体超氧化物的产生。DHPG还通过一种需要mGluR5、IP3和ROS的机制增加疼痛相关的发声和脊髓反射。联合应用ERK(U0126)和PKA(KT5720)抑制剂可完全阻断ROS供体(TBOOH)的兴奋作用。PKC抑制剂(GF109203X)对此无作用。拮抗剂和抑制剂本身并不影响神经元的兴奋性。这些结果提示新的mGluR5-IP3-ROS-ERK/PKA信号通路在杏仁核痛机制中起重要作用。
Reactive oxygen species (ROS) such as superoxide are emerging as important signaling molecules in physiological plasticity but also in peripheral and spinal cord pain pathology. Underlying mechanisms and pain-related ROS signaling in the brain remain to be determined. Neuroplasticity in the amygdala plays a key role in emotional-affective pain responses and depends on group I metabotropic glutamate receptors (mGluRs) and protein kinases. Using patch-clamp, live-cell imaging, and behavioral assays we tested the hypothesis that mitochondrial ROS links group I mGluRs to protein kinase activation to increase neuronal excitability and pain behavior. Agonists for mGluR1/5 (DHPG) or mGluR5 (CHPG) increased neuronal excitability of neurons in the laterocapsular division of the central nucleus of the amygdala (CeLC). DHPG effects were inhibited by an mGluR5 antagonist (MTEP), IP3-receptor blocker (xestospongin C) or ROS scavengers (PBN, tempol), but not by an mGluR1 antagonist (LY367385) or NO synthase inhibitor (L-NAME). Tempol inhibited the effects of IP3 but not those of a PKC activator, indicating that ROS activation was IP3-mediated. Live-cell imaging in CeLC-containing brain slices directly showed DHPG-induced and synaptically evoked mitochondrial superoxide production. DHPG also increased pain-related vocalizations and spinal reflexes through a mechanism that required mGluR5, IP3 and ROS. Combined application of inhibitors of ERK (U0126) and PKA (KT5720) was necessary to block completely the excitatory effects of a ROS donor (tBOOH). A PKC inhibitor (GF109203X) had no effect. Antagonists and inhibitors alone did not affect neuronal excitability. The results suggest an important role for the novel mGluR5-IP3-ROS-ERK/PKA signaling pathway in amygdala pain mechanisms.