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Expression and Cellular Localization of Subunit Proteins of ATP-sensitive K+ Channels

ATP 敏感 K 通道亚基蛋白的表达和细胞定位

基本信息

批准号：
11670675
负责人：
MURAKAMI Tomoyuki
金额：
$ 1.98万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670675/
关键词：
K_<ATP> Channel Mitochondria Cellular Localization K_<ATP>チャネル

项目摘要

The cardiac ATP-sensitive potassium (K_<ATP>) channel plays a crucial role in the cardioprotection induced by preconditioning. The surface channel is thought to be a complex composed of an inward rectifier potassium channel (Kir6.1 and/or Kir6.2) subunit and the sulfonylurea receptor (SUR2A). Recently, although its composition has not yet been identified, the mitochondrial K_<ATP>channel has been paid attention as a key effector of preconditioning. We demonstrated prolonged myocardial ischemia specifically upregulated Kir6.1 mRNA and its protein not only in the ischemic region but also in the non-ischemic region in rat hearts. In contrast, transcriptional and protein levels for Kir6.2 and SUR2A remained unchanged. We also showed that stress-induced release of tissue Ang II is responsible for the specific induction of cardiac Kir6.1 mRNA and protein expression under myocardial ischemia. Confocal microscopic examination demonstrated Kir6.x and Kir6.1+SUR2A are non-specifically expressed in the membrane and cytosole of COS7 cells, while Kir6.x+SUR1 and Kir6.2+SUR2A are specifically expressed in the membrane alone. In contrast, none of combinations of Kir6.x+SURx are expressed in the mitochondria. We also studied the cardioprotective effects of diazoxide, a specific mitochondrial K_<ATP> channel opener, and cromakalim, a non-specific K_<ATP> channel opener in rabbits. Cromakalim, but not diazoxide, limited the infarct-size induced by prolonged myocardial ischemia. Moreover, glibenclamide, a non-specific K_<ATP> channel antagonist, inhibited the infarct-size limiting effect of preconditioning. These studies revealed that surface K_<ATP> channel composed of Kir6.2+SUR2A plays an important role in the cardioprotection. However, potential cardioprotective role of Kir6.2/Kir6.1+SUR2A needs further examination.

心肌ATP敏感性钾<ATP>通道在预处理的心肌保护作用中起重要作用。表面通道被认为是由内向整流钾通道（Kir6.1和/或Kir6.2）亚基和磺酰脲受体（SUR 2A）组成的复合物。近年来，线粒体钾<ATP>通道作为一种重要的预适应效应器而受到关注，但其组成成分尚未明确。我们证明，长期心肌缺血特异性上调Kir6.1 mRNA及其蛋白不仅在缺血区域，而且在非缺血区域在大鼠心脏。相反，Kir6.2和SUR 2A的转录和蛋白水平保持不变。我们还发现，应力诱导的组织Ang II的释放是负责在心肌缺血心脏Kir6.1 mRNA和蛋白表达的特异性诱导。共聚焦显微镜检查显示Kir6.x和Kir6.1+ SUR 2A在COS 7细胞膜和胞浆中非特异性表达，而Kir6.x+ SUR 1和Kir6.2+ SUR 2A仅在膜中特异性表达。相反，Kir6.x+SURx的组合在线粒体中均不表达。本实验还研究了线粒体钾通道特异性开放剂二氮嗪<ATP>和非特异性开放剂克罗卡林<ATP>对家兔心肌的保护作用。Cromakalim，而不是二氮嗪，限制了心肌缺血引起的梗死面积。非特异性钾通道拮抗剂格列本脲<ATP>可抑制预处理的心肌梗死范围限制作用。这些研究表明，<ATP>由Kir6.2+ SUR 2A组成的表面钾通道在心肌保护中起重要作用。然而，Kir6.2/Kir6.1+ SUR 2A的潜在心脏保护作用需要进一步研究。