Potentiation of acid-sensing ion channel activity by peripheral group I metabotropic glutamate receptor signaling
Potentiation of acid-sensing ion channel activity by peripheral group I metabotropic glutamate receptor signaling
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通过外周 I 类代谢型谷氨酸受体信号增强酸敏感离子通道活性
DOI：
10.1016/j.phrs.2016.02.018
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发表时间：
2016-05-01
影响因子：
9.3
通讯作者：
Hu, Wang-Ping
中科院分区：
文献类型：
--
作者：
Gan, Xiong;Wu, Jing;Hu, Wang-Ping
谷氨酸激活外周I组代谢型谷氨酸受体（mGluR）并促进炎性疼痛。然而，它仍然不清楚的机制参与组I mGluR介导的外周敏化。在此，我们报告说，I组mGluRs信号敏化背根神经节（DRG）神经元的酸敏感离子通道（ASIC），并有助于酸中毒诱发的疼痛。DHPG是一种选择性I组mGluR激动剂，可增强ASICs的功能活性，ASICs介导质子诱导事件。DHPG浓度依赖性地增加背根节神经元的质子门控电流。它使质子浓度-响应曲线上移，对质子的最大电流响应增加47.3 +/- 7.0%。I组mGluR，尤其是mGluR 5，通过细胞内级联介导DHPG的增强作用。DHPG对质子门控电流的增强作用在抑制细胞内G（q/11）蛋白、PLC β、PKC或PICK 1信号传导后消失。此外，DHPG增强质子诱发的大鼠DRG神经元的膜兴奋性，并增加由酸刺激引起的去极化幅度和峰电位的数量。最后，外周注射DHPG剂量依赖性地加剧大鼠足底注射乙酸的伤害性反应。I组mGluR信号在大鼠DRG神经元中增强ASIC活性揭示了I组mGluR参与痛觉过敏的一种新的外周机制。(C)2016爱思唯尔有限公司版权所有。
Glutamate activates peripheral group I metabotropic glutamate receptors (mGluRs) and contributes to inflammatory pain. However, it is still not clear the mechanisms are involved in group I mGluRmediated peripheral sensitization. Herein, we report that group I mGluRs signaling sensitizes acid-sensing ion channels (ASICs) in dorsal root ganglion (DRG) neurons and contributes to acidosis-evoked pain. DHPG, a selective group I mGluR agonist, can potentiate the functional activity of ASICs, which mediated the proton-induced events. DHPG concentration-dependently increased proton-gated currents in DRG neurons. It shifted the proton concentration-response curve upwards, with a 47.3 +/- 7.0% increase of the maximal current response to proton. Group I mGluRs, especially mGluR5, mediated the potentiation of DHPG via an intracellular cascade. DHPG potentiation of proton-gated currents disappeared after inhibition of intracellular G(q/11) proteins, PLC beta, PKC or PICK1 signaling. Moreover, DHPG enhanced proton-evoked membrane excitability of rat DRG neurons and increased the amplitude of the depolarization and the number of spikes induced by acid stimuli. Finally, peripherally administration of DHPG dose-dependently exacerbated nociceptive responses to intraplantar injection of acetic acid in rats. Potentiation of ASIC activity by group I mGluR signaling in rat DRG neurons revealed a novel peripheral mechanism underlying group I mGluRs involvement in hyperalgesia. (C) 2016 Elsevier Ltd. All rights reserved.