Orai1 Plays a Crucial Role in Central Sensitization by Modulating Neuronal Excitability
Orai1 Plays a Crucial Role in Central Sensitization by Modulating Neuronal Excitability
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DOI：
10.1523/jneurosci.3007-17.2017
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发表时间：
2018-01-24
影响因子：
5.3
通讯作者：
Hu, Huijuan
中科院分区：
文献类型：
--
作者：
Dou, Yannong;Xia, Jingsheng;Hu, Huijuan
病理性疼痛是一种常见的和衰弱的条件，往往是管理不善。中枢敏感化是病理性疼痛的重要机制。然而，参与中枢致敏的候选分子仍不清楚。钙池操纵的钙通道（SOC）在非兴奋性和兴奋性细胞中介导重要的钙信号。SOC与多种人类病理生理状况有关，包括免疫缺陷、闭塞性血管疾病和癌症。然而，SOC在CNS疾病中的作用相对未被探索。Orai 1是SOC的关键成分，在人类和啮齿动物脊髓背角中表达，但其在背角神经元中的功能意义知之甚少。在这里，我们试图探索Orai 1在调节神经元兴奋性和A型钾通道参与疼痛可塑性的潜在作用。使用雄性和雌性Orai 1基因敲除小鼠，我们发现Orai 1的激活增加了神经元的兴奋性，并通过蛋白激酶C-细胞外信号调节蛋白激酶（PKC-ERK）途径减少了背角神经元中的A型钾通道。Orai 1缺陷显著降低了伤害性刺激引起的急性疼痛，几乎消除了福尔马林诱导的伤害性反应的第二阶段，显著减弱了角叉菜胶诱导的同侧疼痛超敏反应，并消除了角叉菜胶诱导的对侧机械异常性疼痛。一致的是，角叉菜胶诱导的神经元兴奋性的增加被取消在Orai 1突变小鼠的背角。这些发现揭示了一个新的信号通路参与疼痛过程和中枢敏化。我们的研究还揭示了Orai 1，ERK，A型钾通道和神经元兴奋性之间的新联系。
Pathological pain is a common and debilitating condition that is often poorly managed. Central sensitization is an important mechanism underlying pathological pain. However, candidate molecules involved in central sensitization remain unclear. Store-operated calcium channels (SOCs) mediate important calcium signals in nonexcitable and excitable cells. SOCs have been implicated in a wide variety of human pathophysiological conditions, including immunodeficiency, occlusive vascular diseases, and cancer. However, the role of SOCs in CNS disorders has been relatively unexplored. Orai1, a key component of SOCs, is expressed in the human and rodent spinal cord dorsal horn, but its functional significance in dorsal horn neurons is poorly understood. Here we sought to explore a potential role of Orai1 in the modulation of neuronal excitability and A-type potassium channels involved in pain plasticity. Using both male and female Orai1 knock-out mice, we found that activation of Orai1 increased neuronal excitability and reduced A-type potassium channels via the protein kinase C-extracellular signal-regulated protein kinase (PKC-ERK) pathway in dorsal horn neurons. Orai1 deficiency significantly decreased acute pain induced by noxious stimuli, nearly eliminated the second phase of formalin-induced nociceptive response, markedly attenuated carrageenan-induced ipsilateral pain hypersensitivity and abolished carrageenan-induced contralateral mechanical allodynia. Consistently, carrageenan-induced increase in neuronal excitability was abolished in the dorsal horn from Orai1 mutant mice. These findings uncover a novel signaling pathway involved in the pain process and central sensitization. Our study also reveals a novel link among Orai1, ERK, A-type potassium channels, and neuronal excitability.