Histamine Sensitization of the Voltage-Gated Sodium Channel Nav1.7 Contributes to Histaminergic Itch in Mice
Histamine Sensitization of the Voltage-Gated Sodium Channel Nav1.7 Contributes to Histaminergic Itch in Mice
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电压门控钠通道 Nav1.7 的组胺敏化导致小鼠组胺能瘙痒
DOI：
10.1021/acschemneuro.2c00012
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发表时间：
2022-03-02
影响因子：
5
通讯作者：
Zhang, Fan
中科院分区：
文献类型：
--
作者：
Li, Shaoheng;Ding, Meihuizi;Zhang, Fan
瘙痒是许多皮肤病常见的临床症状，严重影响患者的生活质量。Nav1.7是主要在初级感觉神经元中表达的电压门控钠通道亚型，负责触发动作电位（AP）产生的阈值电流的放大。Nav1.7的功能获得性突变导致阵发性瘙痒，而Nav1.7的药理学抑制则加重组胺依赖性瘙痒。然而，组胺和Nav1.7之间导致瘙痒的串扰是不明显的。在本研究中，我们证明了在由化合物48/80诱导的组胺依赖性瘙痒模型小鼠的背根神经节（DRG）神经元中，河豚毒素敏感性（TTX-S）而非TTX抗性Na+电流在比来自媒介物处理的小鼠的DRG神经元的超极化膜电位下被激活。同时，组胺使TTX-S Na+电流的激活电压向超极化方向移动，AP频率增加，引起AP所需的电流阈值降低。进一步的机制研究表明，选择性激活H1而非H2和H4受体模拟组胺对DRG神经元TTX-S Na+通道的作用。蛋白激酶C（PKC）抑制剂GO 8963（而不是PICA抑制剂H89）使组胺致敏的TTX-S Na+通道正常化。我们还证明，组胺转移的激活电压的Na+电流的超极化方向在中国仓鼠卵巢（CHO）细胞表达Nav1.7。重要的是，PF-05089771对Nav1.7的选择性抑制显著缓解了化合物48/80诱导的组胺依赖性瘙痒模型中的抓挠频率。综上所述，这些数据表明，组胺激活H1受体通过DRG神经元中的PKC途径使Nav1.7通道敏感，从而导致组胺依赖性瘙痒。
Itch, a common dinical symptom of many skin diseases, severely impairs the life quality of patients. Nav1.7, a subtype of voltage-gated sodium channels mainly expressed in primary sensory neurons, is responsible for the amplification of threshold currents that trigger action potential (AP) generation. Gain-of-function mutation of Nav1.7 leads to paroxysmal itch, while pharmacological inhibition of Nav1.7 alleviates histamine-dependent itch. However, the crosstalk between histamine and Nav1.7 that leads to itch is undear. In the present study, we demonstrated that in the dorsal root ganglion (DRG) neurons from histaminedependent itch model mice induced by compound 48/80, tetrodotoxin-sensitive (TTX-S) but not TTX-resistant Na+ currents were activated at more hyperpolarized membrane potentials compared to those on DRG neurons from vehicle-treated mice. Meanwhile, bath application of histamine shifted the activation voltages of TTX-S Na+ currents to the hyperpolarized direction, increased the AP frequency, and reduced the current threshold required to elicit APs. Further mechanistic studies demonstrated that selective activation of H1 but not H2 and H4 receptors mimicked histamine effect on TTX-S Na+ channels in DRG neurons. The protein kinase C (PKC) inhibitor GO 8963, but not the PICA inhibitor H89, normalized histamine-sensitized TTX-S Na+ channels. We also demonstrated that histamine shifted the activation voltages of Na+ currents to the hyperpolarized direction in Chinese hamster ovary (CHO) cells expressing Nav1.7. Importantly, selective inhibition of Nav1.7 by PF-05089771 significantly relieved the scratching frequency in a histamine-dependent itch model induced by compound 48/80. Taken together, these data suggest that activation of H1 receptors by histamine sensitizes Nav1.7 channels through the PKC pathway in DRG neurons that contributes to histamine-dependent itch.