Non‐proton ligand‐sensing domain of acid‐sensing ion channel 3 is required for itch sensation

Itch, the unpleasant sensation that evokes a desire to scratch, accompanies numerous skin and nervous system disorders. However, the molecular mechanisms of itch are unclear. Acid‐sensing ion channel 3 ( ASIC 3) is a sensor of acidic and primary inflammatory pain. The whole‐cell patch clamp technique was used to determine the effect of chloroquine ( CQ ) on ASIC s currents in primary sensory neurons or the Chinese hamster ovary cells transfected with rat ASIC 1a or ASIC 3. Site‐directed mutagenesis of plasmid was performed. Scratching behavior was evaluated by measuring the number of bouts during 30 min after injection. CQ , an anti‐malarial drug defined as a histamine‐independent pruritogen, selectively enhanced the sustained phase of ASIC 3 current in a concentration‐dependent manner either in ASIC 3‐transfected Chinese hamster ovary cells or in primary cultured rat dorsal root ganglion neurons. Further studies revealed that the effect of CQ on ASIC 3 channels depends on the newly identified non‐proton ligand‐sensing domain. Importantly, CQ ‐evoked scratching behavior was largely alleviated by APET x2, a selective ASIC 3 channel blocker. Like CQ , other compounds such as amiloride, 2‐guanidine‐4‐methylquinazoline and neuropeptide FF , which have been previously reported to be non‐proton ligands that activate ASIC 3, undoubtedly evoked the scratching response. In conclusion, ASIC 3, a proton‐gated ion channel critical for pain sensation, also functions as an essential component of itch transduction.