Extracellular Spermine Exacerbates Ischemic Neuronal Injury through Sensitization of ASIC1a Channels to Extracellular Acidosis
文献类型：期刊论文
| 作者 | Duan, Bo ; Wang, Yi-Zhi ; Yang, Tao ; Chu, Xiang-Ping ; Yu, Ye ; Huang, Yu ; Cao, Hui ; Hansen, Jillian ; Simon, Roger P. ; Zhu, Michael X. ; Xiong, Zhi-Gang ; Xu, Tian-Le(徐天乐) |
| 刊名 | JOURNAL OF NEUROSCIENCE
 |
| 出版日期 | 2011 |
| 卷号 | 31期号:6页码:2101-2112 |
| ISSN号 | 0270-6474 |
| 关键词 | SENSING ION-CHANNEL CEREBRAL-ISCHEMIA HIPPOCAMPAL-NEURONS INDUCED NEUROTOXICITY POLYAMINE TRANSPORT ACTIVATED CURRENTS RAT-BRAIN CALCIUM RECEPTOR CONTRIBUTES |
| 通讯作者 | Xu, TL (reprint author), Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Neurosci, 320 Yue Yang Rd, Shanghai 200031, Peoples R China,tlxu@ion.ac.cn |
| 英文摘要 | Ischemic brain injury is a major problem associated with stroke. It has been increasingly recognized that acid-sensing ion channels (ASICs) contribute significantly to ischemic neuronal damage, but the underlying mechanism has remained elusive. Here, we show that extracellular spermine, one of the endogenous polyamines, exacerbates ischemic neuronal injury through sensitization of ASIC1a channels to extracellular acidosis. Pharmacological blockade of ASIC1a or deletion of the ASIC1 gene greatly reduces the enhancing effect of spermine in ischemic neuronal damage both in cultures of dissociated neurons and in a mouse model of focal ischemia. Mechanistically, spermine profoundly reduces desensitization of ASIC1a by slowing down desensitization in the open state, shifting steady-state desensitization to more acidic pH, and accelerating recovery between repeated periods of acid stimulation. Spermine-mediated potentiation of ASIC1a activity is occluded by PcTX1 (psalmotoxin 1), a specific ASIC1a inhibitor binding to its extracellular domain. Functionally, the enhanced channel activity is accompanied by increased acid-induced neuronal membrane depolarization and cytoplasmic Ca(2+) overload, which may partially explain the exacerbated neuronal damage caused by spermine. More importantly, blocking endogenous spermine synthesis significantly attenuates ischemic brain injury mediated by ASIC1a but not that by NMDA receptors. Thus, extracellular spermine contributes significantly to ischemic neuronal injury through enhancing ASIC1a activity. Our data suggest new neuroprotective strategies for stroke patients via inhibition of polyamine synthesis and subsequent spermine-ASIC interaction. |
| 学科主题 | Neurosciences & Neurology |
| 资助信息 | National Natural Science Foundation of China[30830035, 30700145]; National Basic Research Program of China[2011CBA00408]; Shanghai Municipal Government[09XD1404900]; National Institutes of Health[R01 NS049470, R01 NS047506, R01 NS050610, R01 GM081658]; K. C. Wong Education Foundation (Hong Kong) |
| 收录类别 | SCI |
| 语种 | 英语 |
| 公开日期 | 2012-07-13 |
| 源URL | [http://ir.sibs.ac.cn/handle/331001/1553]  |
| 专题 | 上海神经科学研究所_神经所(总) |
| 推荐引用方式 GB/T 7714 | Duan, Bo,Wang, Yi-Zhi,Yang, Tao,et al. Extracellular Spermine Exacerbates Ischemic Neuronal Injury through Sensitization of ASIC1a Channels to Extracellular Acidosis[J]. JOURNAL OF NEUROSCIENCE,2011,31(6):2101-2112. |
| APA | Duan, Bo.,Wang, Yi-Zhi.,Yang, Tao.,Chu, Xiang-Ping.,Yu, Ye.,...&Xu, Tian-Le.(2011).Extracellular Spermine Exacerbates Ischemic Neuronal Injury through Sensitization of ASIC1a Channels to Extracellular Acidosis.JOURNAL OF NEUROSCIENCE,31(6),2101-2112. |
| MLA | Duan, Bo,et al."Extracellular Spermine Exacerbates Ischemic Neuronal Injury through Sensitization of ASIC1a Channels to Extracellular Acidosis".JOURNAL OF NEUROSCIENCE 31.6(2011):2101-2112. |
入库方式： OAI收割
来源：上海神经科学研究所
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