The mechanism of temperature-activation of TRP ion channels

Duke University, Durham NC

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Abstract

? 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.