Calmodulin is responsible for Ca(2+)-dependent regulation of TRPA1 Channels.
Calmodulin is responsible for Ca(2+)-dependent regulation of TRPA1 Channels.
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DOI：
10.1038/srep45098
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发表时间：
2017-03-23
影响因子：
4.6
通讯作者：
Zhang X
中科院分区：
文献类型：
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作者：
Hasan R;Leeson-Payne AT;Jaggar JH;Zhang X
TRPA 1是一种Ca 2+渗透性离子通道，参与许多感觉障碍，如疼痛、瘙痒和神经病变。值得注意的是，TRPA 1的功能依赖于Ca 2+，低Ca 2+增强和高Ca 2+失活TRPA 1。然而，目前尚不清楚Ca 2+如何发挥这种对比效应。在这里，我们表明，Ca 2+调节TRPA 1通过钙调素，结合TRPA 1在Ca 2+依赖的方式。在低Ca ~（2+）条件下，钙调素结合可增强TRPA_1的敏感性和Ca ~（2+）诱发的TRPA_1增强作用，而在高Ca ~（2+）条件下，钙调素结合可抑制TRPA_1的敏感性并促进TRPA_1的脱敏作用。钙依赖性增强和失活的TRPA 1被选择性地阻止通过破坏的羧基叶的钙调蛋白与钙调蛋白结合结构域中的C-末端的TRPA 1的相互作用。因此，钙调素是一个关键的Ca 2+传感器，使TRPA 1响应不同的Ca 2+信号不同。
TRPA1 is a Ca2+-permeable ion channel involved in many sensory disorders such as pain, itch and neuropathy. Notably, the function of TRPA1 depends on Ca2+, with low Ca2+ potentiating and high Ca2+ inactivating TRPA1. However, it remains unknown how Ca2+ exerts such contrasting effects. Here, we show that Ca2+ regulates TRPA1 through calmodulin, which binds to TRPA1 in a Ca2+-dependent manner. Calmodulin binding enhanced TRPA1 sensitivity and Ca2+-evoked potentiation of TRPA1 at low Ca2+, but inhibited TRPA1 sensitivity and promoted TRPA1 desensitization at high Ca2+. Ca2+-dependent potentiation and inactivation of TRPA1 were selectively prevented by disrupting the interaction of the carboxy-lobe of calmodulin with a calmodulin-binding domain in the C-terminus of TRPA1. Calmodulin is thus a critical Ca2+ sensor enabling TRPA1 to respond to diverse Ca2+ signals distinctly.