Nitric oxide activates TRP channels by cysteine S-nitrosylation
Nitric oxide activates TRP channels by cysteine S-nitrosylation
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DOI：
10.1038/nchembio821
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发表时间：
2006-11-01
影响因子：
14.8
通讯作者：
Mori, Yasuo
中科院分区：
文献类型：
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作者：
Yoshida, Takashi;Inoue, Ryuji;Mori, Yasuo
瞬时受体电位（TRP）蛋白形成质膜阳离子通道，作为传感器的各种细胞刺激。在这里，我们报告了一种新的激活机制介导的半胱氨酸S-亚硝基化的TRP通道。TRPC和TRPV家族的重组TRPC 1、TRPC 4、TRPC 5、TRPV 1、TRPV 3和TRPV 4通常被分类为受体激活通道和热敏通道，它们响应于一氧化氮（NO）诱导Ca 2+进入细胞。使用半胱氨酸突变体的标记和功能测定，以及在激活反应性二硫化物的膜侧性，表明胞质可访问的Cys 553和附近的Cys 558是介导TRPC 5中NO敏感性的亚硝基化位点。响应性TRP蛋白在孔区域的相同N-末端侧具有保守的半胱氨酸。值得注意的是，天然TRPC 5在G蛋白偶联的ATP受体刺激后的亚硝基化促进Ca 2+进入内皮细胞。这些发现揭示了TRP通道中NO敏感激活门的结构基序，并表明NO传感器是一种新的功能类别的细胞受体，扩展到不同的TRP家族。
Transient receptor potential (TRP) proteins form plasma-membrane cation channels that act as sensors for diverse cellular stimuli. Here, we report a novel activation mechanism mediated by cysteine S-nitrosylation in TRP channels. Recombinant TRPC1, TRPC4, TRPC5, TRPV1, TRPV3 and TRPV4 of the TRPC and TRPV families, which are commonly classified as receptor-activated channels and thermosensor channels, induce entry of Ca2+ into cells in response to nitric oxide (NO). Labeling and functional assays using cysteine mutants, together with membrane sidedness in activating reactive disulfides, show that cytoplasmically accessible Cys553 and nearby Cys558 are nitrosylation sites mediating NO sensitivity in TRPC5. The responsive TRP proteins have conserved cysteines on the same N-terminal side of the pore region. Notably, nitrosylation of native TRPC5 upon G protein-coupled ATP receptor stimulation elicits entry of Ca2+ into endothelial cells. These findings reveal the structural motif for the NO-sensitive activation gate in TRP channels and indicate that NO sensors are a new functional category of cellular receptors extending over different TRP families.