The mechanism of temperature-activation of TRP ion channels

TRP离子通道温度激活机制

• 批准号: 8882612
• 负责人: Jorg Grandl
• 金额: $ 34.42万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8882612
• 关键词: Affect; Afferent Neurons; Amino Acids; Analgesics; Ankyrin Repeat; Architecture; Binding Sites; Chemicals; Coupled; Cysteine; Data; Development; Esthesia; Family; FarGo; Goals; Heating; Inflammatory; Ion Channel; Knowledge; Libraries; Ligand Binding; Measures; Mechanics; Mediating; Methods; Molecular; Mus; Neurons; Nociception; Outcome; Pain; Research; Resolution; Series; Signal Transduction; Site; Structure; TRPV1 gene; Temperature; Temperature Sense; Testing; Tissues; Work; base; cold temperature; crosslink; deep sequencing; experience; extreme temperature; mutant; novel; public health relevance; receptor; research study; sensor; sensory mechanism; voltage

 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.

 描述（由申请人提供）：疼痛和机械温度感在分子水平上还没有得到很好的理解。人们早就知道感觉神经元介导温度和疼痛的感觉。温度到电信号的转换由几个瞬时受体电位（TRP）离子通道介导。这些离子通道被电压、化学物质和冷或热的温度激活。虽然离子通道通过电压或化学物质的激活在原则上是理解的，但通道通过温度激活的分子机制是未知的。理解激活机制的重要的第一步将是识别特定参与温度激活的结构域。第二个重要的步骤是了解温度活化后的构象变化。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，以调节通道活性。在这里，我建议确定域，足以温度激活，并了解温度激活后的构象变化。这些知识将推进对温度激活离子通道的基本理解，并实现开发镇痛药物的最终目标。