ASIC3 Mediates Itch Sensation in Response to Coincident Stimulation by Acid and Nonproton Ligand

•Acidosis enhances certain pruritogenic itch via ASIC3•Pruritogen SL-NH2 acts at ASIC3 to slow channel desensitization•Compounds that cause sustained ASIC3 currents induce an itch response•ASIC3 is critical for scratching behavior and pathological changes in chronic itch

SummaryThe regulation and mechanisms underlying itch sensation are complex. Here, we report a role for acid-sensing ion channel 3 (ASIC3) in mediating itch evoked by certain pruritogens during tissue acidosis. Co-administration of acid with Ser-Leu-Ile-Gly-Arg-Leu-NH2 (SL-NH2) increased scratching behavior in wild-type, but not ASIC3-null, mice, implicating the channel in coincident detection of acidosis and pruritogens. Mechanistically, SL-NH2 slowed desensitization of proton-evoked currents by targeting the previously identified nonproton ligand-sensing domain located in the extracellular region of ASIC3 channels in primary sensory neurons. Ablation of the ASIC3 gene reduced dry-skin-induced scratching behavior and pathological changes under conditions with concomitant inflammation. Taken together, our data suggest that ASIC3 mediates itch sensation via coincident detection of acidosis and nonproton ligands that act at the nonproton ligand-sensing domain of the channel.

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