Abstract
The molecular basis of the thermal sensitivity of temperature-sensitive channels appears to arise from a specific protein domain rather than integration of global thermal effects. Using systematic chimeric analysis, we show that the N-terminal region that connects ankyrin repeats to the first transmembrane segment is crucial for temperature sensing in heat-activated vanilloid receptor channels. Changing this region both transformed temperature-insensitive isoforms into temperature-sensitive channels and significantly perturbed temperature sensing in temperature-sensitive wild-type channels. Swapping other domains such as the transmembrane core, the C terminus, and the rest of the N terminus had little effect on the steepness of temperature dependence. Our results support that thermal transient receptor potential channels contain modular thermal sensors that confer the unprecedentedly strong temperature dependence to these channels.