Variable Threshold of Trigeminal Cold-Thermosensitive Neurons Is Determined by a Balance between TRPM8 and Kv1 Potassium Channels
Variable Threshold of Trigeminal Cold-Thermosensitive Neurons Is Determined by a Balance between TRPM8 and Kv1 Potassium Channels
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DOI：
10.1523/jneurosci.4778-08.2009
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发表时间：
2009-03-11
影响因子：
5.3
通讯作者：
Viana, Felix
中科院分区：
文献类型：
--
作者：
Madrid, Rodolfo;de la Pena, Elvira;Viana, Felix
冷热感受器阈值差异的分子决定因素尚不清楚。在这里，我们表明这种差异与 I-KD 和 I-TRPM8（一种冷激活兴奋性电流）的相对表达相关。I-KD 是一种依赖于 Shaker 样 Kv1 通道的电流，可充当兴奋性制动器。对微小温度变化做出反应的神经元具有 TRPM8（瞬时受体电位阳离子通道，M 亚家族，成员 8）的高功能表达和 IKD 的低表达。相比之下，较低温度激活的神经元 TRPM8 表达较低，IKD 显着。除此之外，两个亚群具有几乎相同的膜和放电特性，表明它们属于同一神经元池。阻断 IKD 会将冷敏感神经元的阈值转移到更高的温度，并增强小鼠中冷诱发的伤害反应。在 TRPA1(-/-) 小鼠中观察到 IKD 阻断的类似行为效应。此外，只有一小部分三叉神经冷敏感神经元被TRPA1激动剂激活，这表明TRPA1在生理条件下未受伤的体细胞冷特异性热感觉神经元检测低温方面并没有发挥主要作用。总的来说，这些发现表明，无害的清凉感和寒冷不适是由特定的低阈值和高阈值冷热感受器神经元发出的信号，其主要区别在于它们对神经元兴奋性具有拮抗作用的两个离子通道的相对表达。因此，尽管TRPM8似乎在大多数外周感觉神经元中充当关键的冷传感器，但相同终端中Kv1通道的表达似乎在冷诱发的不适和疼痛的外周门控中发挥重要作用。
Molecular determinants of threshold differences among cold thermoreceptors are unknown. Here we show that such differences correlate with the relative expression of I-KD, a current dependent on Shaker-like Kv1 channels that acts as an excitability brake, and I-TRPM8, a cold-activated excitatory current. Neurons responding to small temperature changes have high functional expression of TRPM8 (transient receptor potential cation channel, subfamily M, member 8) and low expression of IKD. In contrast, neurons activated by lower temperatures have a lower expression of TRPM8 and a prominent IKD. Otherwise, both subpopulations have nearly identical membrane and firing properties, suggesting that they belong to the same neuronal pool. Blockade of IKD shifts the threshold of cold-sensitive neurons to higher temperatures and augments cold-evoked nocifensive responses in mice. Similar behavioral effects of IKD blockade were observed in TRPA1(-/-) mice. Moreover, only a small percentage of trigeminal cold-sensitive neurons were activated by TRPA1 agonists, suggesting that TRPA1 does not play a major role in the detection of low temperatures by uninjured somatic cold-specific thermosensory neurons under physiological conditions. Collectively, these findings suggest that innocuous cooling sensations and cold discomfort are signaled by specific low- and high-threshold cold thermoreceptor neurons, differing primarily in their relative expression of two ion channels having antagonistic effects on neuronal excitability. Thus, although TRPM8 appears to function as a critical cold sensor in the majority of peripheral sensory neurons, the expression of Kv1 channels in the same terminals seem to play an important role in the peripheral gating of cold-evoked discomfort and pain.