Functional properties and toxin pharmacology of a dorsal root ganglion sodium channel viewed through its voltage sensors.
Functional properties and toxin pharmacology of a dorsal root ganglion sodium channel viewed through its voltage sensors.
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DOI：
10.1085/jgp.201110614
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发表时间：
2011-07
期刊：
影响因子：
--
通讯作者：
Swartz KJ
中科院分区：
文献类型：
--
作者：
Bosmans F;Puopolo M;Martin-Eauclaire MF;Bean BP;Swartz KJ
电压激活钠(NAV)通道Nav1.9在背根节(DRG)神经元中表达，被认为在伤害性感受中起重要作用。在揭示这种非规范NAV通道的功能特性和药理敏感性方面进展缓慢，因为试图在异源表达系统中表达该通道的尝试没有成功。在这里，我们使用蛋白质工程的方法来剖析四个Nav1.9电压传感器对通道功能和药理学的贡献。我们在每个电压传感器中定义了单独的S3b-S4桨基序，并表明当它们被移植到电压激活的钾通道中时，它们可以感知膜电压的变化并驱动电压传感器的激活。我们还发现，Nav1.9中的桨基序是动物毒素的靶点，这些毒素改变了Nav1.9介导的DRG神经元电流。我们的结果表明，缓慢激活和失活Nav1.9通道具有与标准NAV通道相同的功能和药理学特性，但也显示出独特的药理敏感性，可潜在地用于开发新的疼痛治疗方法。
The voltage-activated sodium (Nav) channel Nav1.9 is expressed in dorsal root ganglion (DRG) neurons where it is believed to play an important role in nociception. Progress in revealing the functional properties and pharmacological sensitivities of this non-canonical Nav channel has been slow because attempts to express this channel in a heterologous expression system have been unsuccessful. Here, we use a protein engineering approach to dissect the contributions of the four Nav1.9 voltage sensors to channel function and pharmacology. We define individual S3b–S4 paddle motifs within each voltage sensor, and show that they can sense changes in membrane voltage and drive voltage sensor activation when transplanted into voltage-activated potassium channels. We also find that the paddle motifs in Nav1.9 are targeted by animal toxins, and that these toxins alter Nav1.9-mediated currents in DRG neurons. Our results demonstrate that slowly activating and inactivating Nav1.9 channels have functional and pharmacological properties in common with canonical Nav channels, but also show distinctive pharmacological sensitivities that can potentially be exploited for developing novel treatments for pain.
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影响因子：
16.2
作者：
Aggarwal, SK;MacKinnon, R
通讯作者：
MacKinnon, R
影响因子：
13.8
作者：
Bosmans F;Swartz KJ
通讯作者：
Swartz KJ
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作者：
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作者：
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64.8
作者：
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通讯作者：
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