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Extracellular Spermine Exacerbates Ischemic Neuronal Injury through Sensitization of ASIC1a Channels to Extracellular Acidosis

txq01001 添加于 2011-2-21 21:19 | 1874 次阅读 | 0 个评论

作者
Duan B, Wang Y-Z, Yang T, Chu X-P, Yu Y, Huang Y, Cao H, Hansen J, Simon RP, Zhu MX, Xiong Z-G, Xu T-L
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.
详细资料
- 文献种类:期刊
- 期刊名称: The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
- 期刊缩写: J Neurosci
- 期卷页: 2011年第31卷第6期 2101-2112页
- 地址: Institute of Neuroscience and State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China, Robert S. Dow Neurobiology Laboratories, Legacy Research, Portland, Oregon 97232, Department of Neurobiology, Morehouse School of Medicine, Atlanta, Georgia 30310, and Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, Texas 77030
- ISBN: 0270-6474
- 备注:PMID:21307247
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附件
Extracellular Spermine Exacerbates Ischemic Neuronal Injury through Sensitizatio
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