A role of acid-sensing ion channels in ischemia

描述（由申请人提供）：缺血性损伤引起即刻和 大脑pH值显著下降，其后果是多重和复杂的， 不完全理解。质子门控阳离子通道的新发现 （酸敏感离子通道，ASIC）在大脑中提供了一个新的机会， 探索迄今为止未知的生物学方面， 大脑对局部缺血的反应。ASIC系统在 缺血我们的初步数据显示，脑特异性ASIC 2a的上调 缺血后ASIC亚基和另一个ASIC亚基在脑中的共定位 线粒体，缺血性坏死期间扰动的主要部位， 凋亡在膜片钳实验中，培养的新皮层细胞显示出 酸诱发电流与ASIC 1a的酸诱发电流相匹配，其性质在 体外缺血和神经元（PC 12）细胞显示酸诱发电流， 用ASIC亚基特异性拮抗剂阻断。因此我们建议 1)表征所有ASIC亚基在局灶性和全局性治疗后的表达， 缺血; 2）鉴定和比较正常人中ASIC亚基-蛋白质相互作用 3）描述ASIC亚单位的亚细胞定位; 电生理学评价缺血对ASIC功能的影响 以及ASIC活性对缺血性损伤转归的影响。这些新颖 这些研究可能会对脑缺血的生物学提供新的理解 并为治疗干预提供新的靶点。

DESCRIPTION (provided by applicant): Ischemic injury causes an immediate and marked fall in brain pH, the consequences of which are multiple and complex and incompletely understood. The recent discovery of proton-gated cation channels (acid-sensing ion channels, ASIC) in the brain offers a novel opportunity to explore hitherto unknown aspects of biology relevant to understanding the response of the brain to ischemia. The ASIC system does respond during ischemia. Our preliminary data show up-regulation of the brain-specific ASIC2a subunit following ischemia and co-localization of another ASIC subunit to brain mitochondria, a major site of perturbation during ischemic necrosis and apoptosis. In patch-clamping experiments, cultured neocortical cells showed an acid-evoked current matching that of ASIC1a, whose properties changed after in vitro ischemia, and neuronal (PC12) cells displayed an acid-evoked current that was blocked with an ASIC subunit-specific antagonist. We therefore propose to 1) characterize the expression of all ASIC subunits after focal and global ischemia; 2) identify and compare ASIC subunit-protein interactions in normal and ischemic brain; 3) describe the sub-cellular location of the ASIC subunits; and 4) assess electrophysiologically the effect of ischemia on ASIC function and the effect of ASIC activity on the outcome of ischemic injury. These novel studies are likely to offer new understanding of the biology of brain ischemia and offer new targets for therapeutic intervention.