The Role of Kv7/M Potassium Channels in Controlling Ectopic Firing in Nociceptors.
The Role of Kv7/M Potassium Channels in Controlling Ectopic Firing in Nociceptors.
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DOI：
10.3389/fnmol.2017.00181
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发表时间：
2017
影响因子：
4.8
通讯作者：
Binshtok AM
中科院分区：
文献类型：
--
作者：
Barkai O;Goldstein RH;Caspi Y;Katz B;Lev S;Binshtok AM
外周伤害性神经元编码并向中枢神经系统传递诱导损伤的刺激。在正常情况下，严格控制伤害性静息电位可防止其自发激活。然而，在许多病理条件下，膜电位的控制被破坏，导致伤害性神经元异位、与刺激无关的放电，这与自发性疼痛相关。我们研究了 KV7/M 通道在稳定膜电位和阻止伤害性神经元自发放电中的作用。这些通道产生低电压激活、非失活的 M 型 K+ 电流（M 电流，IM），控制神经元的兴奋性。使用培养的大鼠伤害感受器样背根神经节神经元的穿孔贴片记录，我们表明抑制 M 电流会导致伤害感受神经元去极化并产生重复放电。为了评估作用于伤害性末端的 M 电流在多大程度上能够稳定末端的膜电位，从而防止其异位激活，在正常和病理条件下，我们建立了一个具有真实末端树的伪单极无髓鞘伤害性神经元的多室计算模型。建模的末端树基于伤害性外周末端的体内结构，我们通过对支配小鼠后爪的表达 GFP 的伤害性神经元末端进行体内多光子成像来评估。通过修改建模终端树（终端 gKV7/M）处 KV7/M 通道的电导，我们发现 40% 的终端 gKV7/M 电导足以防止自发放电，而约 75% 的终端 gKV7/M 足以抑制刺激诱导的伤害性神经元激活。此外，我们发现末端 M 电流降低了伤害性神经元对膜电位微小波动的敏感性。此外，我们模拟了终末持续钠电流和 M 电流之间的相互作用如何影响神经元的兴奋性。我们证明，即使当末端 Na(V)1.9 通道电导大幅增加时，伤害性神经元中的末端 M 电流也会阻碍自发放电。另一方面，当末端 gKV7/M 减少时，末端 Na(V)1.9 电导略有增加后，伤害性神经元会自发放电。我们的结果强调了 M 电流在稳定膜电位方面的关键作用，从而在正常和病理条件下控制伤害性自发放电方面的关键作用。
Peripheral nociceptive neurons encode and convey injury-inducing stimuli toward the central nervous system. In normal conditions, tight control of nociceptive resting potential prevents their spontaneous activation. However, in many pathological conditions the control of membrane potential is disrupted, leading to ectopic, stimulus-unrelated firing of nociceptive neurons, which is correlated to spontaneous pain. We have investigated the role of KV7/M channels in stabilizing membrane potential and impeding spontaneous firing of nociceptive neurons. These channels generate low voltage-activating, noninactivating M-type K+ currents (M-current, IM), which control neuronal excitability. Using perforated-patch recordings from cultured, rat nociceptor-like dorsal root ganglion neurons, we show that inhibition of M-current leads to depolarization of nociceptive neurons and generation of repetitive firing. To assess to what extent the M-current, acting at the nociceptive terminals, is able to stabilize terminals' membrane potential, thus preventing their ectopic activation, in normal and pathological conditions, we built a multi-compartment computational model of a pseudo-unipolar unmyelinated nociceptive neuron with a realistic terminal tree. The modeled terminal tree was based on the in vivo structure of nociceptive peripheral terminal, which we assessed by in vivo multiphoton imaging of GFP-expressing nociceptive neuronal terminals innervating mice hind paw. By modifying the conductance of the KV7/M channels at the modeled terminal tree (terminal gKV7/M) we have found that 40% of the terminal gKV7/M conductance is sufficient to prevent spontaneous firing, while ~75% of terminal gKV7/M is sufficient to inhibit stimulus induced activation of nociceptive neurons. Moreover, we showed that terminal M-current reduces susceptibility of nociceptive neurons to a small fluctuations of membrane potentials. Furthermore, we simulated how the interaction between terminal persistent sodium current and M-current affects the excitability of the neurons. We demonstrated that terminal M-current in nociceptive neurons impeded spontaneous firing even when terminal Na(V)1.9 channels conductance was substantially increased. On the other hand, when terminal gKV7/M was decreased, nociceptive neurons fire spontaneously after slight increase in terminal Na(V)1.9 conductance. Our results emphasize the pivotal role of M-current in stabilizing membrane potential and hereby in controlling nociceptive spontaneous firing, in normal and pathological conditions.