TRPM8 voltage sensor mutants reveal a mechanism for integrating thermal and chemical stimuli
TRPM8 voltage sensor mutants reveal a mechanism for integrating thermal and chemical stimuli
复制标题
DOI：
10.1038/nchembio862
复制
发表时间：
2007-03-01
影响因子：
14.8
通讯作者：
Nilius, Bernd
中科院分区：
文献类型：
--
作者：
Voets, Thomas;Owsianik, Grzegorz;Nilius, Bernd
TRPM8是瞬时受体电位（TRP）通道超家族的成员，在热敏神经元中表达，在热敏神经元中起冷和薄荷醇传感器的作用。TRPM8和大多数其他温度敏感TRP通道（thermotrp）是电压门控的；温度和配体通过改变激活的电压依赖性来调节通道打开。热trps的门控机制和结构目前尚不清楚。在这里，我们发现人类TRPM8的跨膜片段4 （S4）和S4- s5连接体中的电荷中和突变减少了通道的门控电荷，这表明该区域是电压传感器的一部分。诱变引起的电压敏感性变化转化为热敏性的改变，从而建立了电压和温度传感之间的严格耦合。该区域的特异性突变也会影响薄荷醇的亲和力，这表明薄荷醇与TRPM8电压传感器之间存在直接相互作用。基于这些发现，我们提出了一个monod - wyman - changeux型模型来解释电压、温度和薄荷醇对TRPM8门控的综合影响。
TRPM8, a member of the transient receptor potential (TRP) channel superfamily, is expressed in thermosensitive neurons, in which it functions as a cold and menthol sensor. TRPM8 and most other temperature-sensitive TRP channels (thermoTRPs) are voltage gated; temperature and ligands regulate channel opening by shifting the voltage dependence of activation. The mechanisms and structures underlying gating of thermoTRPs are currently poorly understood. Here we show that charge-neutralizing mutations in transmembrane segment 4 (S4) and the S4-S5 linker of human TRPM8 reduce the channel's gating charge, which indicates that this region is part of the voltage sensor. Mutagenesis-induced changes in voltage sensitivity translated into altered thermal sensitivity, thereby establishing the strict coupling between voltage and temperature sensing. Specific mutations in this region also affected menthol affinity, which indicates a direct interaction between menthol and the TRPM8 voltage sensor. Based on these findings, we present a Monod-Wyman-Changeux-type model explaining the combined effects of voltage, temperature and menthol on TRPM8 gating.