LAUSR

Significance Thermoregulation in the mammalian body is mediated by a central brain thermostat. Because deep-brain temperatures are maintained within a narrow range, the thermostat must contain a sensor that can differentiate temperature fluctuations as small as ±1°C around 37°C. No protein with such intrinsic properties is currently known. Recently, the ligand-gated ion channel TRPM2 was identified as pivotal for thermoregulation, but it is unclear whether the intrinsic properties of TRPM2 itself or temperature dependence of its agonist concentrations is responsible. Here, we show that the TRPM2 protein intrinsically possesses the unique properties essential for a deep brain temperature sensor: exceptional response-steepness and an optimal threshold. We uncover two unusual molecular mechanisms that serve to achieve that aim in a protein-autonomous manner.