The mechanism of temperature-activation of TRP ion channels

TRP离子通道温度激活机制

• 批准号: 9043211
• 负责人: Jorg Grandl
• 金额: $ 34.52万
• 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/9043211
• 关键词: Affect; Afferent Neurons; Amino Acids; Analgesics; Ankyrin Repeat; Architecture; Binding Sites; Chemicals; Coupled; Cysteine; Data; Development; Esthesia; Family; FarGo; Goals; Health; 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; 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被很好地理解。人们很早就知道感觉神经元介导温度和疼痛感。温度到电信号的转换是由多种介导的。瞬时受体电位 (TRP) 离子通道。这些离子通道由电压、化学物质以及冷或热温度激活。虽然原则上了解电压或化学物质激活离子通道，但温度激活通道的分子机制尚不清楚。重要的第一步。了解激活机制将是识别专门参与温度激活的域，第二个重要步骤是了解温度激活时的构象变化，第三步也是最后一步是开发针对该机制的策略和化合物。在这里，我建议识别足以进行温度激活的域，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理解，并实现最终目标。开发镇痛药物。