Ion Channel Profile of TRPM8 Cold Receptors Reveals a Role of TASK-3 Potassium Channels in Thermosensation

•BAC transgenesis was used to label TRPM8-expressing cold thermoreceptors in mice•The ion channel transcriptome of purified cold thermoreceptors was analyzed•TRPM8 cold receptors express high levels of pH-sensitive TASK-3 potassium channels•Inactivation of TASK-3 channels decreased the cold pain threshold in living mice

SummaryAnimals sense cold ambient temperatures through the activation of peripheral thermoreceptors that express TRPM8, a cold- and menthol-activated ion channel. These receptors can discriminate a very wide range of temperatures from innocuous to noxious. The molecular mechanism responsible for the variable sensitivity of individual cold receptors to temperature is unclear. To address this question, we performed a detailed ion channel expression analysis of cold-sensitive neurons, combining bacterial artificial chromosome (BAC) transgenesis with a molecular-profiling approach in fluorescence-activated cell sorting (FACS)-purified TRPM8 neurons. We found that TASK-3 leak potassium channels are highly enriched in a subpopulation of these sensory neurons. The thermal threshold of TRPM8 cold neurons is decreased during TASK-3 blockade and in mice lacking TASK-3, and, most importantly, these mice display hypersensitivity to cold. Our results demonstrate a role of TASK-3 channels in thermosensation, showing that a channel-based combinatorial strategy in TRPM8 cold thermoreceptors leads to molecular specialization and functional diversity.

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