Oxidative challenges sensitize the capsaicin receptor by covalent cysteine modification
Oxidative challenges sensitize the capsaicin receptor by covalent cysteine modification
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DOI：
10.1073/pnas.0902675106
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发表时间：
2009-11-24
影响因子：
11.1
通讯作者：
Lin, Stephanie
中科院分区：
文献类型：
--
作者：
Chuang, Huai-hu;Lin, Stephanie
辣椒素受体TRPV1是痛觉通路中的主要传导通道之一，它整合来自细胞外环境的信息以控制初级伤害感受神经元的兴奋性。TRPV1的致敏性增强了对中度有害甚至无害刺激的疼痛感觉。我们在这里报告，氧化应激显着敏感TRPV1在多个物种的直系同源。致敏作用可以在切除的由内而外的膜贴片中重现，通过强还原剂逆转，并通过用烷基化半胱氨酸的马来酰亚胺预处理来阻断。我们确定了多个半胱氨酸所需的充分调节TRPV1的氧化挑战。强大的氧化调节恢复受体的激动剂敏感性脱敏延长暴露于辣椒素。此外，氧化调节与激酶或质子调节协同作用。因此，氧化调节是通过进化上保守的半胱氨酸的共价修饰来调节TRPV 1活性的一种强大机制，并且可能在炎症、感染或组织损伤期间的疼痛感知过程中发挥作用。
The capsaicin receptor TRPV1, one of the major transduction channels in the pain pathway, integrates information from extracellular milieu to control excitability of primary nociceptive neurons. Sensitization of TRPV1 heightens pain sensation to moderately noxious or even innocuous stimuli. We report here that oxidative stress markedly sensitizes TRPV1 in multiple species' orthologs. The sensitization can be recapitulated in excised inside-out membrane patches, reversed by strong reducing agents, and blocked by pretreatment with maleimide that alkylates cysteines. We identify multiple cysteines required for full modulation of TRPV1 by oxidative challenges. Robust oxidative modulation recovers the agonist sensitivity of receptors desensitized by prolonged exposure to capsaicin. Moreover, oxidative modulation operates synergistically with kinase or proton modulations. Thus, oxidative modulation is a robust mechanism tuning TRPV1 activity via covalent modification of evolutionarily conserved cysteines and may play a role in pain sensing processes during inflammation, infection, or tissue injury.