Chloroquine impairs visual transduction via modulation of acid sensing ion channel 1a
Chloroquine impairs visual transduction via modulation of acid sensing ion channel 1a
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氯喹通过调节酸感应离子通道 1a 损害视觉转导
DOI：
10.1016/j.toxlet.2014.05.008
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发表时间：
2014-08-04
影响因子：
3.5
通讯作者：
Li, Jingxin
中科院分区：
文献类型：
--
作者：
Li, Xiaoyu;Fei, Jianchun;Li, Jingxin
酸敏感离子通道（Acid-sensing ion channels，ASIC）是细胞外的pH传感器，由质子激活，其影响视网膜活动和光转导。在所有ASIC中，ASIC 1a在视网膜中大量表达，并参与正常的视网膜活动。氯喹已被用于治疗疟疾、类风湿性关节炎和系统性红斑狼疮，但已被证明对视网膜有毒。然而，其潜在机制仍不清楚。本研究通过测量视网膜电图（ERG）来研究氯喹在光转导中的作用。采用全细胞膜片钳技术，观察氯喹对大鼠视网膜神经节细胞（RGNS）和转染ASIC 1a的中国仓鼠卵巢（CHO）细胞酸诱发电流的影响。氯喹降低了暗视0.01和明视3.0的b波和振荡电位（OPs）的振幅，这一效应几乎完全被PcTx 1（一种ASIC 1a特异性通道阻滞剂）逆转。此外，膜片钳实验表明，氯喹降低了峰值电流的幅度，延长了ASIC 1a电流的激活和脱敏。氯喹对ASIC 1a动力学的影响具有剂量依赖性、pH依赖性和Ca ~（2+）依赖性。综上所述，这些结果表明，氯喹影响视觉传导直接修改ASIC 1a的动力学。这种机制，可以部分解释氯喹的视网膜毒性。(C)2014爱思唯尔爱尔兰有限公司版权所有。
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 la were dose-, pH- and Ca2+-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. (C) 2014 Elsevier Ireland Ltd. All rights reserved.