Nature：感测疼痛的机制

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Nature：感测疼痛的机制 Scripps研究院的研究人员发现名为TRPA1的蛋白质能传送痛觉讯号，也就是说它是许多毒性或刺激性化合物的感应器。科学家ArdemPatapoutian表示：这些毒性化合物能直接或间接的与TRPA1蛋白的cysteine胺基酸结合，TRPA1的活化作用与化合物的入侵有直接的关系。此研究发表于1月21日的Nature期刊。Cysteines是组成蛋白质的二十个胺基酸之一，能够进行氧化及还原作用，也

   Scripps 研究院的研究人员发现名为TRPA1的蛋白质能传送痛觉讯号，也就是说它是许多毒性或刺激性化合物的感应器。科学家Ardem Patapoutian表示：这些毒性化合物能直接或间接的与TRPA1蛋白的cysteine胺基酸结合，TRPA1的活化作用与化合物的入侵有直接的关系。此研究发表于1月21日的Nature期刊。  

  Cysteines是组成蛋白质的二十个胺基酸之一，能够进行氧化及还原作用，也许TRPA1的cysteine天生就很容易被修饰，任何能与cysteine反应的试剂都能活化TRPA1。虽然目前对cysteine修饰与离子通道活化间的机制仍不清楚，但是一般来说，化合物活化离子通道是以锁与钥机制(lock-and-key mechanism)来进行，两者通常都具有蛋白质结构的相似性，然而，毒性化合物活化TRAP1的机制却完全不以此机制进行，一旦毒性化合物与TRPA1结合就不分开。  

   研究人员也发现另一个称为KEAP1(Kelch-like ECH-associated protein 1) 的蛋白质，也会受到cysteine修饰试剂的活化，是自由基造成氧化伤害的感测蛋白。目前，各大药厂也都将TRAP1视为慢性疼痛的目标蛋白，希望更了解TRPA1与疼痛的机制以开发治疗慢性疼痛的药物。


部分英文原文：

Noxious compounds activate TRPA1 ion channels through covalent modification of cysteines
Lindsey J. Macpherson1, Adrienne E. Dubin1,2, Michael J. Evans1, Felix Marr3,5, Peter G. Schultz3,4, Benjamin F. Cravatt1,3 and Ardem Patapoutian1,4

Department of Cell Biology,
Department of Molecular Biology,
Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, USA
Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA
Present address: Westf鋖ische Wilhelms-Universit鋞 Münster, Schlossplatz 2, D-48149, Münster, Germany.
Correspondence to: Ardem Patapoutian1,4 Correspondence and requests for materials should be addressed to A.P. (Email: ardem@scripps.edu).


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The nervous system senses peripheral damage through nociceptive neurons that transmit a pain signal1, 2. TRPA1 is a member of the Transient Receptor Potential (TRP) family of ion channels and is expressed in nociceptive neurons3, 4, 5. TRPA1 is activated by a variety of noxious stimuli, including cold temperatures, pungent natural compounds, and environmental irritants6, 7, 8, 9, 10, 11. How such diverse stimuli activate TRPA1 is not known. We observed that most compounds known to activate TRPA1 are able to covalently bind cysteine residues. Here we use click chemistry to show that derivatives of two such compounds, mustard oil and cinnamaldehyde, covalently bind mouse TRPA1. Structurally unrelated cysteine-modifying agents such as iodoacetamide (IA) and (2-aminoethyl)methanethiosulphonate (MTSEA) also bind and activate TRPA1. We identified by mass spectrometry fourteen cytosolic TRPA1 cysteines labelled by IA, three of which are required for normal channel function. In excised patches, reactive compounds activated TRPA1 currents that were maintained at least 10 min after washout of the compound in calcium-free solutions. Finally, activation of TRPA1 by disulphide-bond-forming MTSEA is blocked by the reducing agent dithiothreitol (DTT). Collectively, our data indicate that covalent modification of reactive cysteines within TRPA1 can cause channel activation, rapidly signalling potential tissue damage through the pain pathway.

更多原文链接：

http://www.nature.com/nature/jou ... bs/nature05544.html