有害化合物通过对氨酸的共价修饰来激活TRPA1离子通道
Lindsey J Macpherson1, Adrienne E Dubin, Michael J Evans
1Department of Cell Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
Nature
|January 24, 2007
概括
由刺激物激活的TRPA1通道,通过共价修饰的氨酸残留物信号疼痛. 这种共价结合,特别是反应性囊素,触发了通道激活和疼痛信号.
科学领域:
- 神经科学是一个神经科学.
- 分子生物学分子生物学
- 生物化学 生物化学
背景情况:
- 无感受神经元检测到外围损伤,通过神经系统传输疼痛信号.
- TRPA1 (过时受体潜在通道A1) 在感知神经元中表达,并被各种有害刺激 (如寒冷和刺激物) 激活.
- 通过各种刺激激活TRPA1的确切机制仍然在很大程度上是未知的.
研究的目的:
- 调查氨酸残留物共价修饰在TRPA1通道激活中的作用.
- 为了阐明多种刺激如何激活TRPA1通道.
主要方法:
- 利用点击化学来证明末油和 cinnamaldehyde衍生物对小鼠TRPA1.1的共价结合.
- 使用乙胺 (IA) 和 (2-aminoethyl) methanethiosulphonate (MTSEA) 等氨酸修饰剂来探测TRPA1的激活.
- 使用质谱学识别了涉及通道功能的特定TRPA1氨酸残留物.
- 在切除的补丁中进行了电生理学记录,以评估TRPA1电流以及反应化合物,洗和还原剂 (DTT) 的作用.
主要成果:
- 末油和 cinnamaldehyde衍生物对老鼠TRPA1.1进行共价结合.
- 结构不相关的代理IA和MTSEA也绑定和激活TRPA1.
- 质谱检测确定了14种细胞质TRPA1囊蛋白被IA修改,其中3种对正常功能至关重要.
- 反应化合物诱导的TRPA1电流在冲洗后保持;MTSEA诱导的激活被DTT阻断.
结论:
- 在TRPA1中对反应性半氨酸的共价修饰是通道激活的关键机制.
- 这种共价变异通过疼痛通路快速发出潜在组织损伤的信号.
- 了解TRPA1的囊反应性,可以了解疼痛信号和潜在的治疗点.
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