title: Chloroquine impairs visual transduction via modulation of acid sensing ion channel 1a.
abstract: Acid-sensing ion channels (ASICs) are extracellular pH sensors activated by protons, which influence retinal activity and phototransduction. Among all ASICs, ASIC1a is abundantly expressed in the retina and involved in normal retinal activity. Chloroquine, which has been used in the treatment of malaria, rheumatoid arthritis and systemic lupus erythematosus, has been shown to be toxic to the retina. However, the underlying mechanisms remain unclear. In this study, we investigated the role of chloroquine in phototransduction by measuring the electroretinogram (ERG). The effect of chloroquine on acid-evoked currents in either isolated rat retinal ganglion neurons (RGNs) or Chinese hamster ovary (CHO) cells transfected with ASIC1a were assessed using a whole-cell patch-clamp technique. Chloroquine reduced the b-wave of scotopic 0.01 and photopic 3.0 and amplitudes of oscillatory potentials (OPs), an effect which was almost completely reversed by PcTx1, an ASIC1a-specific channel blocker. Further, patch-clamp experiments demonstrated that chloroquine reduced the peak current amplitude and prolonged the activation and desensitization of ASIC1a currents. These chloroquine-induced effects on the kinetics of ASIC 1a were dose-, pH- and Ca(2+)-dependent. Taken together, these results demonstrate that chloroquine affects vision conduction by directly modifying the kinetics of ASIC1a. Such a mechanism, may, in part, explain the retinal toxicity of chloroquine.
authors.affiliation: Institute of Physiology, Shandong Univerisity School of Medicine, 44#,Wenhua Xi Road, Jinan, Shandong, 250012 PR China.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Anesthesiology, Qilu Hospital, Shandong University, 107#, Wenhua Xi Road, Jinan, 250012 PR China.
authors.forename: Jianchun
authors.initials: J
authors.lastname: Fei
authors.affiliation: Department of Anesthesiology, Qilu Hospital, Shandong University, 107#, Wenhua Xi Road, Jinan, 250012 PR China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Lei
authors.affiliation: Institute of Physiology, Shandong Univerisity School of Medicine, 44#,Wenhua Xi Road, Jinan, Shandong, 250012 PR China.
authors.forename: Kejing
authors.initials: K
authors.lastname: Liu
authors.affiliation: Department of Anesthesiology, Qilu Hospital, Shandong University, 107#, Wenhua Xi Road, Jinan, 250012 PR China.
authors.forename: Jianbo
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Anesthesiology, Qilu Hospital, Shandong University, 107#, Wenhua Xi Road, Jinan, 250012 PR China.
authors.forename: Tao
authors.initials: T
authors.lastname: Meng
authors.affiliation: Department of Anesthesiology, Qilu Hospital, Shandong University, 107#, Wenhua Xi Road, Jinan, 250012 PR China.
authors.forename: Jingui
authors.initials: J
authors.lastname: Yu
authors.affiliation: Institute of Physiology, Shandong Univerisity School of Medicine, 44#,Wenhua Xi Road, Jinan, Shandong, 250012 PR China. Electronic address: ljingxin@sdu.edu.cn.
authors.forename: Jingxin
authors.initials: J
authors.lastname: Li
mesh_terms: D062565:Acid Sensing Ion Channels / Q000187:drug effects* / Q000378:metabolism; D000200:Action Potentials; D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002738:Chloroquine / Q000633:toxicity*; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D004596:Electroretinography; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008297:Male; D018408:Patch-Clamp Techniques; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D012165:Retinal Ganglion Cells / Q000187:drug effects* / Q000378:metabolism; D014162:Transfection; D014785:Vision, Ocular / Q000187:drug effects*
chemical_list: D062565:Acid Sensing Ion Channels; C568268:Asic1 protein, rat; D002738:Chloroquine; D002118:Calcium
keywords: Chloroquine; ERG; acid-sensing ion channel; retinal toxicity; visual transduction