TRP channel activation by reversible covalent modification
TRP channel activation by reversible covalent modification
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DOI：
10.1073/pnas.0609598103
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发表时间：
2006-12-19
影响因子：
11.1
通讯作者：
Julius, David
中科院分区：
文献类型：
--
作者：
Hinman, Andrew;Chuang, Huai-hu;Julius, David
异硫氰酸烯丙酯，芥末和其他芥末油的辛辣成分，通过激活TRPA1（感觉神经末梢上的兴奋性离子通道）产生疼痛。异硫氰酸酯是膜可渗透的亲电体，与硫醇和伯胺形成加合物，这表明共价修饰，而不是经典的锁和钥匙结合，解释了它们的激动剂特性。事实上，我们表明，硫醇反应性化合物的不同结构激活TRPA1的方式，依赖于共价修饰的半胱氨酸残基内的细胞质N末端的通道。这些发现表明了一种不寻常的范式，即天然产物通过直接，可逆和共价蛋白质修饰激活受体。
Allyl isothiocyanate, the pungent principle of wasabi and other mustard oils, produces pain by activating TRPA1, an excitatory ion channel on sensory nerve endings. Isothiocyanates are membrane-permeable electrophiles that form adducts with thiols and primary amines, suggesting that covalent modification, rather than classical lock-and-key binding, accounts for their agonist properties. Indeed, we show that thiol reactive compounds of diverse structure activate TRPA1 in a manner that relies on covalent modification of cysteine residues within the cytoplasmic N terminus of the channel. These findings suggest an unusual paradigm whereby natural products activate a receptor through direct, reversible, and covalent protein modification.