IQGAP1 promotes chronic pain by regulating the trafficking and sensitization of TRPA1 channels.
IQGAP1 promotes chronic pain by regulating the trafficking and sensitization of TRPA1 channels.
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DOI：
10.1093/brain/awac462
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发表时间：
2023-06-01
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影响因子：
--
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中科院分区：
文献类型：
--
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TRPA1通道与慢性疼痛的机械和冷超敏反应有关。但TRPA1如何介导这一过程尚不清楚。在这里，我们表明IQ基序含有GTPase激活蛋白1是负责使用生化，分子，Ca2+成像和行为方法的组合。TRPA1和含有GTPase激活蛋白1的IQ基序相互结合，在小鼠感觉背根神经节神经元中高度共定位。含GTPase激活蛋白1而不含TRPA1的IQ基序在慢性炎症性和神经性疼痛中表达增加。然而，TRPA1通过与含有GTPase激活蛋白1的IQ motif相关的小GTPase Cdc42催化转运到背根神经节神经元膜，导致该通道的功能增敏。蛋白激酶A的激活也足以引起TRPA1的转运和致敏。然而，在缺乏含有GTPase激活蛋白1的IQ基序时，所有这些反应都被完全阻止。同时，含有GTPase激活蛋白1的IQ基序的缺失可显著降低小鼠慢性炎症性和神经性疼痛的机械和冷超敏反应。含有GTPase激活蛋白1的IQ基序因此通过将运输和信号机制与TRPA1通道耦合来促进慢性疼痛。Khan等人研究了TRPA1通道参与机械和冷超敏反应的机制。他们表明，支架蛋白IQGAP1是这一过程的重要组成部分，它与TRPA1通道结合，促进它们在感觉神经元中的运输和功能敏化。
TRPA1 channels have been implicated in mechanical and cold hypersensitivity in chronic pain. But how TRPA1 mediates this process is unclear. Here we show that IQ motif containing GTPase activating protein 1 is responsible using a combination of biochemical, molecular, Ca2+ imaging and behavioural approaches. TRPA1 and IQ motif containing GTPase activating protein 1 bind to each other and are highly colocalized in sensory dorsal root ganglia neurons in mice. The expression of IQ motif containing GTPase activating protein 1 but not TRPA1 is increased in chronic inflammatory and neuropathic pain. However, TRPA1 undergoes increased trafficking to the membrane of dorsal root ganglia neurons catalysed by the small GTPase Cdc42 associated with IQ motif containing GTPase activating protein 1, leading to functional sensitization of the channel. Activation of protein kinase A is also sufficient to evoke TRPA1 trafficking and sensitization. All these responses are, however, completely prevented in the absence of IQ motif containing GTPase activating protein 1. Concordantly, deletion of IQ motif containing GTPase activating protein 1 markedly reduces mechanical and cold hypersensitivity in chronic inflammatory and neuropathic pain in mice. IQ motif containing GTPase activating protein 1 thus promotes chronic pain by coupling the trafficking and signalling machineries to TRPA1 channels. Khan et al. study the mechanisms by which TRPA1 channels contribute to mechanical and cold hypersensitivity. They show that the scaffold protein IQGAP1 is an essential part of this process, binding to TRPA1 channels and promoting their trafficking and functional sensitization in sensory neurons.
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影响因子：
5.6
作者：
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通讯作者：
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DOI：
10.1016/j.bbrc.2007.05.029
发表时间：
2007-07-13
影响因子：
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影响因子：
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