The mechanism of temperature-activation of TRP ion channels

 描述(申请人提供)：疼痛和机械温度的感觉在分子水平上没有被很好地理解。人们很早就知道感觉神经元调节温度和痛觉。温度到电信号的转换是由几个瞬时受体电位(Trp)离子通道介导的。这些离子通道被电压、化学物质以及低温或高温所激活。虽然离子通道被电压或化学物质激活原则上是被理解的，但通道被温度激活的分子机制是未知的。了解激活机制的一个重要的第一步是识别特定参与温度激活的结构域。第二个重要的步骤是理解温度活化时的构象变化。第三步也是最后一步是开发针对机制和构象变化的策略和化合物，以调节通道活动。在这里，我建议确定足以进行温度激活的结构域，并了解温度激活时的构象变化。这些知识将促进对温度激活离子通道的基本了解，并使开发止痛药的最终目标成为可能。

 DESCRIPTION (provided by applicant): Pain and the sense of mechanical temperature are not well understood on a molecular level. It has long been known that sensory neurons mediate the sense of temperature and pain. The conversion of temperature into electric signals is mediated by several transient receptor potential (TRP) ion channels. These ion channels are activated by voltage, chemicals and either cold or hot temperatures. Whereas the activation of ion channels by voltage or chemicals is understood in principle, the molecular mechanism of channel activation by temperature is unknown. An important first step in understanding the activation mechanism would be the identification of domains that are specifically involved in temperature activation. The second important step would be the understanding of conformational changes upon temperature- activation. The third and final step would be to develop strategies and compounds that target the mechanism and conformational changes in order to modulate channel activity. Here, I propose to identify domains that are sufficient for temperature activation and to understand conformational changes upon temperature activation. This knowledge will advance the fundamental understanding of temperature activated ion channels and enable the ultimate goal of developing analgesic drugs.