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Molecular analysis of the neuropathic pain state using sns-null mutant mice

使用 sns 无效突变小鼠对神经病理性疼痛状态进行分子分析

基本信息

批准号：
13470313
负责人：
FUJIMOTO Yoshinori
金额：
$ 7.55万
依托单位：
HIROSHIMA UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470313/
关键词：
sodium channel dorsal root ganglion tetrodotoxin channel conductance voltage-clamp patch-clamp

项目摘要

Sensory neurons in dorsal root ganglia (DRG) express at least seven isoforms of voltage-gated sodium channel (VGSC) α-subunits. These isoforms show localized distribution within the primary sensory path-way and probably mediate multiple types of sodium currents (I_<Na>) with different kinetic properties, giving rise to fast, slow or persistent I_<Na>s. However, little is known as to which isoform is responsible for a particular I_<Na> in DRG neurons. We have recently identified two types persistent I_<Na>s : one is resistant to tetrodotoxin (TTX) and found exclusively in small DRG neurons (I_<TTX-R/persist>), and the otner is sensitive to TTX and found in medium/large DRG neurons (I_<TTX-S/persist>). Available data suggest that the former is most likely to be mediated by Na_V1.9, while the latter may be mediated by Na_V1.6. To confirm these possibilities, we performed single cell nested RT-PCR combined with concurrent patch clamp recording and investigated the correlation between mRNA … More expression and phenotype of I_<Na> in an identified DRG neuron. I_<TTX-R/persist> was recorded in isolation from small DRG neurons of Na_V1.8-null mutant mice in the presence of TTX. Most of the small neurons, which were associated with Na_V1.9 transcript, manifested I_<TTX-R/persist>, confirming that the isoform mediating I_<TTX-R/persist> is probably Na_V1.9. Unexpectedly, however, Na_V1.9 was evident also in a considerable number of medium/large neurons that were totally devoid of I_<TTX-R/persist>. These results indicate that I_<TTX-R/persist> is not solely dependent on the level of Na_V1.9 transcript. An intriguing finding was that Na_V1.9 transcript was often absent in small DRG neurons from naive mice while the same transcript was evident in most of the small DRG neurons from mutants. Expression of Na_V1.6 transcript was demonstrated in a considerable portion of the medium/large neurons from both naive and mutant mice. However, these neurons did not consistently manifest I_<TTX-S/persist> suggesting that I_<TTX-S/persist> may not be carried by Na_V1.6. Less

背根神经节（DRG）感觉神经元表达至少7种电压门控钠通道（VGSC）α亚基亚型。这些亚型在初级感觉通路中呈局部分布，可能介导多种不同动力学性质的钠电流（I_s<Na>），产生快、慢或持续的I_<Na>s。然而，很少有人知道，哪种亚型是负责一个特定的<Na>I_2在DRG神经元。我们最近发现了两种类型的持久I_<Na>s：一种是对河豚毒素（TTX）有抗性的，只存在于DRG小神经元（I_<TTX-R/persist>），另一种是对TTX敏感的，存在于DRG中/大神经元（I_<TTX-S/persist>）。现有数据表明，前者最有可能由Na_V1.9介导，而后者可能由Na_V1.6介导。为了证实这些可能性，我们进行了单细胞巢式RT-PCR结合同步膜片钳记录，并研究了mRNA之间的相关性， ...更多信息 I_<Na>在已鉴定的DRG神经元中的表达和表型。在TTX存在下，从Na_V1.8-null突变小鼠的小DRG神经元分离记录I_<TTX-R/persistent>。大多数与Na_V1.9转录本相关的小神经元表现出I_<TTX-R/persistent>，证实了介导I_<TTX-R/persistent>的亚型可能是Na_V1.9。然而，出乎意料的是，Na_V1.9在相当数量的完全缺乏I_<TTX-R/persist>的中型/大型神经元中也是明显的。这些结果表明I_<TTX-R/persistence>并不完全依赖于Na_V1.9转录本的水平。一个有趣的发现是，Na_V1.9转录物在来自幼稚小鼠的小DRG神经元中通常不存在，而相同的转录物在来自突变体的大多数小DRG神经元中是明显的。Na_V1.6转录本的表达在来自幼稚小鼠和突变小鼠的相当一部分中/大神经元中得到证实。然而，这些神经元并不一致地表现出I_<TTX-S/persist>，这表明I_<TTX-S/persist>可能不由Na_V1.6携带。少