Redox-Dependent Modulation of T-Type Ca(2+) Channels in Sensory Neurons Contributes to Acute Anti-Nociceptive Effect of Substance P.
Redox-Dependent Modulation of T-Type Ca(2+) Channels in Sensory Neurons Contributes to Acute Anti-Nociceptive Effect of Substance P.
复制标题
感觉神经元中 T 型 Ca2 通道的氧化还原依赖性调节有助于 P 物质的急性抗伤害作用
DOI：
10.1089/ars.2015.6560
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发表时间：
2016-08-10
影响因子：
6.6
通讯作者：
Gamper N
中科院分区：
文献类型：
--
作者：
Huang D;Huang S;Gao H;Liu Y;Qi J;Chen P;Wang C;Scragg JL;Vakurov A;Peers C;Du X;Zhang H;Gamper N
摘要目的：神经肽P物质(SP)是一类对组织损伤有反应的外周感觉神经元(伤害性感受器)产生和释放的物质。SP在中枢神经系统发挥兴奋作用，但对外周SP的作用仍知之甚少；因此，本文旨在研究这些外周机制。结果：SP可明显抑制伤害性感受器的T型电压门控性钙通道。这种作用是由神经激肽1(NK1)受体诱导的细胞内活性氧(ROS)释放介导的，因为这种作用可以被还原剂二硫苏糖醇阻止或逆转，并被外源性或内源性ROS模拟。这种氧化还原介导的T型钙通道抑制作用是通过调节CaV3.2通道对环境锌的敏感性来实现的，因为它可以被锌离子螯合和外源锌模仿而阻止或逆转。CaV3.2中锌结合位点的消除使该通道对SP介导的抑制不敏感。重要的是，外周应用SP可显著减少体内缓激肽诱导的大鼠伤害性感受；敲除CaV3.2可显著降低这种抗伤害性作用。这一非典型的信号级联反应与前面所述的SP介导的M型K+通道的增强具有相同的初始步骤。创新：我们的研究建立了SP外周抗伤害性效应的机制，通过这种神经肽产生ROS依赖的前痛性T型钙电流抑制和同时增强抗痛性M型K+电流。这些发现将有助于更好地理解内源性镇痛的机制。结论：SP通过依赖氧化还原调节通道对锌的敏感性来调节伤害性感受器的T型通道活动，这一新的调节途径参与了SP的外周抗伤害性效应。抗氧化剂。氧化还原信号。25,233-251。
Abstract Aims: Neuropeptide substance P (SP) is produced and released by a subset of peripheral sensory neurons that respond to tissue damage (nociceptors). SP exerts excitatory effects in the central nervous system, but peripheral SP actions are still poorly understood; therefore, here, we aimed at investigating these peripheral mechanisms. Results: SP acutely inhibited T-type voltage-gated Ca2+ channels in nociceptors. The effect was mediated by neurokinin 1 (NK1) receptor-induced stimulation of intracellular release of reactive oxygen species (ROS), as it can be prevented or reversed by the reducing agent dithiothreitol and mimicked by exogenous or endogenous ROS. This redox-mediated T-type Ca2+ channel inhibition operated through the modulation of CaV3.2 channel sensitivity to ambient zinc, as it can be prevented or reversed by zinc chelation and mimicked by exogenous zinc. Elimination of the zinc-binding site in CaV3.2 rendered the channel insensitive to SP-mediated inhibition. Importantly, peripherally applied SP significantly reduced bradykinin-induced nociception in rats in vivo; knock-down of CaV3.2 significantly reduced this anti-nociceptive effect. This atypical signaling cascade shared the initial steps with the SP-mediated augmentation of M-type K+ channels described earlier. Innovation: Our study established a mechanism underlying the peripheral anti-nociceptive effect of SP whereby this neuropeptide produces ROS-dependent inhibition of pro-algesic T-type Ca2+ current and concurrent enhancement of anti-algesic M-type K+ current. These findings will lead to a better understanding of mechanisms of endogenous analgesia. Conclusion: SP modulates T-type channel activity in nociceptors by a redox-dependent tuning of channel sensitivity to zinc; this novel modulatory pathway contributes to the peripheral anti-nociceptive effect of SP. Antioxid. Redox Signal. 25, 233–251.