Nonproton Ligand Sensing Domain Is Required for Paradoxical Stimulation of Acid-sensing Ion Channel 3 (ASIC3) Channels by Amiloride
文献类型：期刊论文
| 作者 | Li, Wei-Guang ; Yu, Ye ; Huang, Chen ; Cao, Hui ; Xu, Tian-Le(徐天乐) |
| 刊名 | JOURNAL OF BIOLOGICAL CHEMISTRY
 |
| 出版日期 | 2011 |
| 卷号 | 286期号:49页码:42635-42646 |
| 关键词 | GATED CATION CHANNEL NA+ CHANNEL INFLAMMATORY PAIN MOLECULAR-CLONING SENSORY NEURONS CONTRIBUTES CALCIUM MODULATION ISCHEMIA LINKER |
| ISSN号 | 0021-9258 |
| 通讯作者 | Xu, TL (reprint author), 280 S Chongqing Rd, Shanghai 200025, Peoples R China,xu-happiness@shsmu.edu.cn |
| 英文摘要 | Acid-sensing ion channels (ASICs), which belong to the epithelial sodium channel/degenerin family, are activated by extracellular protons and are inhibited by amiloride (AMI), an important pharmacological tool for studying all known members of epithelial sodium channel/degenerin. In this study, we reported that AMI paradoxically opened homomeric ASIC3 and heteromeric ASIC3 plus ASIC1b channels at neutral pH and synergistically enhanced channel activation induced by mild acidosis (pH 7.2 to 6.8). The characteristic profile of AMI stimulation of ASIC3 channels was reminiscent of the channel activation by the newly identified nonproton ligand, 2-guanidine-4-methylquinazoline. Using site-directed mutagenesis, we showed that ASIC3 activation by AMI, but not its inhibitory effect, was dependent on the integrity of the nonproton ligand sensing domain in ASIC3 channels. Moreover, the structure-activity relationship study demonstrated the differential requirement of the 5-amino group in AMI for the stimulation or inhibition effect, strengthening the different interactions within ASIC3 channels that confer the paradoxical actions of AMI. Furthermore, using covalent modification analyses, we provided strong evidence supporting the nonproton ligand sensing domain is required for the stimulation of ASIC3 channels by AMI. Finally, we showed that AMI causes pain-related behaviors in an ASIC3-dependent manner. These data reinforce the idea that ASICs can sense nonproton ligands in addition to protons. The results also indicate caution in the use of AMI for studying ASIC physiology and in the development of AMI-derived ASIC inhibitors for treating pain syndromes. |
| 学科主题 | Biochemistry & Molecular Biology |
| 收录类别 | SCI |
| 资助信息 | National Natural Science Foundation of China[30830035]; National Basic Research Program of China[2011CBA00408]; Shanghai Municipal Government[09XD1404900] |
| 语种 | 英语 |
| 公开日期 | 2012-07-13 |
| 源URL | [http://ir.sibs.ac.cn/handle/331001/1517]  |
| 专题 | 上海神经科学研究所_神经所(总) |
| 推荐引用方式 GB/T 7714 | Li, Wei-Guang,Yu, Ye,Huang, Chen,et al. Nonproton Ligand Sensing Domain Is Required for Paradoxical Stimulation of Acid-sensing Ion Channel 3 (ASIC3) Channels by Amiloride[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2011,286(49):42635-42646. |
| APA | Li, Wei-Guang,Yu, Ye,Huang, Chen,Cao, Hui,&Xu, Tian-Le.(2011).Nonproton Ligand Sensing Domain Is Required for Paradoxical Stimulation of Acid-sensing Ion Channel 3 (ASIC3) Channels by Amiloride.JOURNAL OF BIOLOGICAL CHEMISTRY,286(49),42635-42646. |
| MLA | Li, Wei-Guang,et al."Nonproton Ligand Sensing Domain Is Required for Paradoxical Stimulation of Acid-sensing Ion Channel 3 (ASIC3) Channels by Amiloride".JOURNAL OF BIOLOGICAL CHEMISTRY 286.49(2011):42635-42646. |
入库方式： OAI收割
来源：上海神经科学研究所
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