Analyses of calcium-activated potassium channels as novel targets for new drug therapy

钙激活钾通道作为新药治疗新靶点的分析

基本信息

批准号：
17390045
负责人：
IMAIZUMI Yuji
金额：
$ 10.3万
依托单位：
Nagoya City University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2007
项目状态：
已结题

项目摘要

In excitable cells, such as CNS neurons, negative feedback regulation systems for intracellular Ca^<2+> homeostasis work to prevent Ca^<2+> overlord, when excess excitability and resulting excess Ca^<2+> influx occurs. Activation of Ca^<2+> activated K+ (Kca) channels is know to be one ` of the most important components responsible for the negative feedback regulation of [Ca2^+]_i in excitable cells. This project was undertaken to elucidate the molecular mechanism for the regulation of Kca channel activity and to search changes in the regulation diseases. The goal of this project is to find out molecular seeds targeting on K_ca channels in some diseases. The following development was obtained during the research period. (1) It was found that small conductance K_ca (SK) channel in vascular endothelial cell lines originally derived from bovine blood-brain barrier has significant functional role in endothelial; proliferation stimulated by ATP presumably released from astrocytes in CNS. (J … More BC,2006; J Pharmacol Sci, 104, 2007). (2) The deep impact of ryanodine receptor type2 (RyR2) to the mechanism for negative feedback regulation of [Ca^<2+>], via spontaneous Ca^<2+> release(Ca^<2+> spark) from sarcoplasmic reticulum and subsequent activation of large conductance Kca (BK) channel was found using urinary bladder smooth muscle cells from wild type and RyR2 heterozygous KO mice. A line of evidence indicates that RyR2 contributes to the bladder continent as 'a key molecule regulating resting membrane potential and muscular tonus as well as excitation-contraction coupling (J Physiol, 2007, J Pharmacol Sci, 103, 2007). (3) It was found that potential sensitive oxonol dyes act as potent BK channel openers. It is the first synthesized compound which shows opening property selective to BK81 and 84 subunits over BK62. The oxonol compounds may be a seed of 8 subunit selective BK channel opener (Mol Pharmacol, 2007). (4) It has been known that the contractile responses of isolated large arteries from spontaneously hypertensive rats (SHR) to agonists are markedly potentiated in low pH bathing solution. It was found that the enhanced expression of BK channels in arterial smooth muscles of SHR and its sensitivity to extracellular pH are responsible for the acid pH induced potentiation of contraction (Am J Physiol, 2007). Less

在诸如CNS神经元之类的令人兴奋的细胞中，细胞内Ca^<2+>稳态的负反馈调节系统可防止Ca^<2+>霸主，而当超过令人兴奋并产生的Ca^<2+>会发生。 Ca^<2+>激活的K+（KCA）通道的激活是一种最重要的组件之一，负责在令人兴奋的单元格中[Ca2^+] _ i的负反馈调节。该项目是为了阐明调节KCA通道活性的分子机制并搜索调节疾病的变化。该项目的目的是找出某些疾病中K_CA通道上靶向的分子种子。在研究期间获得了以下发展。（1）发现最初来自牛血脑屏障的血管内皮细胞系中的小电导K_CA（SK）通道在内皮中具有重要的功能作用；大概是由CNS中星形胶质细胞释放的ATP刺激的增殖。（J…More BC，2006; J Pharmacol Sci，104，2007）。（2）通过赞助的Ca^<2+>]的负反馈调节机制的深层影响，通过赞助的Ca^<2+>释放（Ca^<2+> Spark）从肌质网中释放（Ca^<2+> Spark）从肌质网和随后使用大型电导率KCA（bk）的细胞及其后期的细胞和狂热的细胞及其随后的激活而发现了Wild Bladder hyder hyder Musy Musy Musy Musy Musy typer Musy andery hyder kca（bk）。老鼠。一系列证据表明，RYR2有助于膀胱大陆为“关键分子调节静息膜电位和肌肉螺纹，以及兴奋的反应偶联（J Physiol，2007，J Pharmacol SCI，103，2007）。（3）发现潜在敏感的氧醇染料充当潜在的BK通道开瓶。这是第一个合成的化合物，它显示了对BK81的开放属性选择性，而BK62上的84个亚基。氧醇化合物可能是8个亚基选择性BK通道开瓶的种子（Molpharmacol，2007）。（4）众所周知，在低pH沐浴溶液中明显地潜在地潜在地潜在地潜在地潜在地潜在地潜在地潜在地潜在地潜在地潜在地潜在地潜在地潜在地，众所周知，来自赞助者 - 环境高血压大鼠（SHR）的分离大动脉的收缩反应。已经发现，SHR动脉平滑肌肉中BK通道的表达增强及其对细胞外pH的敏感性负责酸pH诱导的收缩潜力（Am J Physiol，2007）。较少的