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.
The sense of temperature is an important component of pain. Several transient receptor potential (TRP) ion channels are activated by hot or cold temperatures and chemicals. Pain can be evoked through activation of TRP channels either by extreme temperatures or under inflammatory conditions by temperatures that are normally perceived as innocuous. TRP channels have therefore become important targets for the development of analgesics. However, the understanding of the mechanistic function of TRP channels is incomplete. This work proposed here will be a significant step towards understanding how hot or cold temperatures activate TRP ion channels mechanistically and might help developing analgesic drugs.
|Hutson, Mary R; Keyte, Anna L; Hernández-Morales, Miriam et al. (2017) Temperature-activated ion channels in neural crest cells confer maternal fever-associated birth defects. Sci Signal 10:|
|Sosa-Pagán, Jason O; Iversen, Edwin S; Grandl, Jörg (2017) TRPV1 temperature activation is specifically sensitive to strong decreases in amino acid hydrophobicity. Sci Rep 7:549|
|Jabba, Sairam; Goyal, Raman; Sosa-Pagán, Jason O et al. (2014) Directionality of temperature activation in mouse TRPA1 ion channel can be inverted by single-point mutations in ankyrin repeat six. Neuron 82:1017-31|