Kv7-specific activators hyperpolarize resting membrane potential and modulate human iPSC-derived sensory neuron excitability.
Kv7-specific activators hyperpolarize resting membrane potential and modulate human iPSC-derived sensory neuron excitability.
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DOI：
10.3389/fphar.2023.1138556
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发表时间：
2023
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
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作者：
慢性疼痛非常普遍，仍然是全球未满足的重大医疗需求。作为寻找赋予疼痛弹性的调节基因的一部分，我们研究了两个家庭队列，其中一个人报告的疼痛比其他家庭成员少得多，这些家庭成员具有相同的致病性功能获得性Nav1.7突变，该突变赋予疼痛信号背根神经节（DRG）神经元过度兴奋性。在每一种运动中，疼痛弹性个体在Kv7.2或Kv7.3中携带功能获得变体，这两种钾通道稳定膜电位并降低兴奋性。我们在这项分子遗传学研究中观察到，这些功能获得性Kv7.2和7.3变体降低了DRG神经元的兴奋性，这表明激活或打开Kv 7通道的药物应该会减弱感觉神经元的放电。在本研究中，我们评估了三种Kv 7调节剂-瑞替加滨（Kv7.2至Kv7.5激活剂）、伊卡-110381（Kv7.2/Kv7.3特异性激活剂）和作为比较物的ML 277（Kv7.1特异性激活剂）-在“人盘中疼痛”模型（人iPSC衍生的感觉神经元，iPSC-SN）中对感觉神经元兴奋性的影响。多电极阵列（MEA）记录证明了瑞替加滨和伊卡-110381（但不是ML 277）对放电的抑制，浓度-响应曲线表明瑞替加滨可以在亚微摩尔浓度下实现放电减少50%。电流钳记录表明，瑞替加滨超极化iPSC-SN静息电位和增加阈值。这项研究暗示Kv7.2/Kv7.3通道是感觉神经元兴奋性的有效调节剂，并表明特异性靶向感觉神经元（包括人类感觉神经元）中Kv7.2/Kv7.3电流的化合物可能提供缓解疼痛的有效方法。
Chronic pain is highly prevalent and remains a significant unmet global medical need. As part of a search for modulatory genes that confer pain resilience, we have studied two family cohorts where one individual reported much less pain than other family members that share the same pathogenic gain-of-function Nav1.7 mutation that confers hyperexcitability on pain-signaling dorsal root ganglion (DRG) neurons. In each of these kindreds, the pain-resilient individual carried a gain-of-function variant in Kv7.2 or Kv7.3, two potassium channels that stabilize membrane potential and reduce excitability. Our observation in this molecular genetic study that these gain-of-function Kv7.2 and 7.3 variants reduce DRG neuron excitability suggests that agents that activate or open Kv7 channels should attenuate sensory neuron firing. In the present study, we assess the effects on sensory neuron excitability of three Kv7 modulators—retigabine (Kv7.2 thru Kv7.5 activator), ICA-110381 (Kv7.2/Kv7.3 specific activator), and as a comparator ML277 (Kv7.1 specific activator)—in a “human-pain-in-a-dish” model (human iPSC-derived sensory neurons, iPSC-SN). Multi-electrode-array (MEA) recordings demonstrated inhibition of firing with retigabine and ICA-110381 (but not with ML277), with the concentration-response curve indicating that retigabine can achieve a 50% reduction of firing with sub-micromolar concentrations. Current-clamp recording demonstrated that retigabine hyperpolarized iPSC-SN resting potential and increased threshold. This study implicates Kv7.2/Kv7.3 channels as effective modulators of sensory neuron excitability, and suggest that compounds that specifically target Kv7.2/Kv7.3 currents in sensory neurons, including human sensory neurons, might provide an effective approach toward pain relief.
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伤害感受神经元体膜电位的控制及其对外周伤害感受传递的影响。
影响因子：
7.4
作者：
Du X;Hao H;Gigout S;Huang D;Yang Y;Li L;Wang C;Sundt D;Jaffe DB;Zhang H;Gamper N
通讯作者：
Gamper N
影响因子：
14.5
作者：
Alsaloum, Matthew;Labau, Julie I. R.;Waxman, Stephen G.
通讯作者：
Waxman, Stephen G.
DOI：
10.1085/jgp.201812070
发表时间：
2018-12-03
期刊：
The Journal of general physiology
影响因子：
--
作者：
Wang CK;Lamothe SM;Wang AW;Yang RY;Kurata HT
通讯作者：
Kurata HT
影响因子：
8.3
作者：
Khanamiri, Saereh;Soltysinska, Ewa;Olesen, Soren-Peter
通讯作者：
Olesen, Soren-Peter
DOI：
10.1124/jpet.109.162800
发表时间：
2010-03-01
影响因子：
3.5
作者：
Iannotti, Fabio Arturo;Panza, Elisabetta;Taglialatela, Maurizio
通讯作者：
Taglialatela, Maurizio