title: Non-proton ligand-sensing domain of acid-sensing ion channel 3 is required for itch sensation.
abstract: 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 (ASIC3) 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 ASICs currents in primary sensory neurons or the Chinese hamster ovary cells transfected with rat ASIC1a or ASIC3. 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 ASIC3 current in a concentration-dependent manner either in ASIC3-transfected Chinese hamster ovary cells or in primary cultured rat dorsal root ganglion neurons. Further studies revealed that the effect of CQ on ASIC3 channels depends on the newly identified non-proton ligand-sensing domain. Importantly, CQ-evoked scratching behavior was largely alleviated by APETx2, a selective ASIC3 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 ASIC3, undoubtedly evoked the scratching response. In conclusion, ASIC3, a proton-gated ion channel critical for pain sensation, also functions as an essential component of itch transduction.
authors: Department of Physiology, School of Medicine, Qilu Hospital, Shandong University, Jinan, Shandong, China.|Department of Anesthesiology, Qilu Hospital, Shandong University, Jinan, Shandong, China.
authors: Zhen
authors: Z
authors: Lei
authors: Institute of Clinical Pharmacology, Qilu Hospital of Shandong University, Jinan, Shandong, China.
authors: Abdul
authors: A
authors: Sami Shaikh
authors: Department of Physiology, School of Medicine, Qilu Hospital, Shandong University, Jinan, Shandong, China.
authors: Wenshuai
authors: W
authors: Zheng
authors: Department of Physiology, School of Medicine, Qilu Hospital, Shandong University, Jinan, Shandong, China.
authors: Xiao
authors: X
authors: Yu
authors: Department of Anesthesiology, Qilu Hospital, Shandong University, Jinan, Shandong, China.
authors: Jingui
authors: J
authors: Yu
authors: Department of Physiology, School of Medicine, Qilu Hospital, Shandong University, Jinan, Shandong, China.
authors: Jingxin
authors: J
authors: Li
mesh_terms: D062565:Acid Sensing Ion Channels / Q000378:metabolism*; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology / Q000633:toxicity; D016466:CHO Cells; D002478:Cells, Cultured; D002738:Chloroquine / Q000494:pharmacology / Q000633:toxicity; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011537:Pruritus / Q000139:chemically induced / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism*
chemical_list: C568269:ASIC3 protein, rat; D062565:Acid Sensing Ion Channels; D000962:Antimalarials; D002738:Chloroquine
keywords: ASIC3; chloroquine; itch; non-proton ligand-sensing domain; sustained currents