Molecular basis for heat desensitization of TRPV1 ion channels
Molecular basis for heat desensitization of TRPV1 ion channels
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TRPV1离子通道热脱敏的分子基础
DOI：
10.1038/s41467-019-09965-6
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发表时间：
2019-05-13
影响因子：
16.6
通讯作者：
Lai, Ren
中科院分区：
文献类型：
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作者：
Luo, Lei;Wang, Yunfei;Lai, Ren
瞬态受体电位香草酸 1 (TRPV1) 离子通道是哺乳动物中有害热量的典型分子传感器。它在持续热响应中的作用仍然知之甚少，因为快速热诱导脱敏（Dh）紧随热诱导激活（Ah）之后。为了了解 Dh 的生理作用和结构基础，我们对小鼠 (mV1) 和天然缺乏 Dh 的鸭嘴兽 (pV1) 中的 TRPV1 通道进行了比较研究。在这里，我们表明 mV1（而非 pV1）的 N 端和 C 端结构域之间的温度敏感相互作用驱动了孔中的构象重排，导致 Dh。我们进一步表明，表达 pV1 的基因敲入小鼠可以正常感知热，但在炎热环境中会遭受烫伤。我们的研究结果表明，Dh 在进化过程中作为一种保护机制进化得很晚，而 Ah 和 Dh 之间的微妙平衡对于哺乳动物感知和响应有害热量至关重要。
The transient receptor potential vanilloid 1 (TRPV1) ion channel is a prototypical molecular sensor for noxious heat in mammals. Its role in sustained heat response remains poorly understood, because rapid heat-induced desensitization (Dh) follows tightly heat-induced activation (Ah). To understand the physiological role and structural basis of Dh, we carried out a comparative study of TRPV1 channels in mouse (mV1) and those in platypus (pV1), which naturally lacks Dh. Here we show that a temperature-sensitive interaction between the N- and C-terminal domains of mV1 but not pV1 drives a conformational rearrangement in the pore leading to Dh. We further show that knock-in mice expressing pV1 sensed heat normally but suffered scald damages in a hot environment. Our findings suggest that Dh evolved late during evolution as a protective mechanism and a delicate balance between Ah and Dh is crucial for mammals to sense and respond to noxious heat.