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

• 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
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17390045/
• 关键词: calcium-activated potassium channel; BK channel; SK channel; potassium channel opener; ryanodine receptor; caveolae; drug development; potential sensitive fluorescent; カルシウム活性化カリウムチャネル; TASKチャネル; ピマル酸; 心筋ミトコンドリア; 心筋保護作用; 間質細胞; ペースメーカー細胞

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

在可兴奋细胞中，例如中枢神经系统神经元，当发生过度兴奋性和由此导致的过量Ca ^ 2+ 流入时，细胞内Ca ^ 2+ 稳态的负反馈调节系统起作用以防止Ca ^ 2+ 霸主。 Ca^2+ 激活的 K+ (Kca) 通道已知是负责可兴奋细胞中 [Ca2^+]_i 负反馈调节的最重要组成部分之一。阐明 Kca 通道活性调节的分子机制并寻找调节疾病的变化 该项目的目标是找出一些疾病中针对 K_ca 通道的分子种子 在研究期间取得了以下进展 1。 ) 发现源自牛血脑屏障的血管内皮细胞系中的小电导 K_ca (SK) 通道在中枢神经系统星形胶质细胞释放的 ATP 刺激下具有显着的功能作用 (J. … 更多 BC,2006; J Pharmacol Sci, 104, 2007) (2) 兰尼碱受体 2 型 (RyR2) 通过自发 Ca^< 对 [Ca^<2+>] 负反馈调节机制的深刻影响使用野生膀胱平滑肌细胞发现肌浆网中的 2+> 释放（Ca^<2+> 火花）以及随后大电导 Kca (BK) 通道的激活一系列证据表明，RyR2 作为“调节静息膜电位和肌肉紧张以及兴奋-收缩耦合的关键分子”对膀胱大陆有贡献（J Physiol，2007，J Pharmacol Sci，103， (2007). 发现潜在敏感的氧杂菁染料可作为有效的 BK 通道开放剂，它是第一个合成的具有选择性开放特性的化合物。氧杂菁化合物可能是 8 亚基选择性 BK 通道开放剂的种子 (Mol Pharmacol, 2007) (4) 已知自发性高血压大鼠 (SHR) 的离体大动脉的收缩反应。 ）对激动剂的作用在低pH沐浴液中显着增强。发现SHR动脉平滑肌中BK通道的表达增强及其敏感性。细胞外 pH 值是酸性 pH 值诱导收缩增强的原因（Am J Physiol，2007）。

项目成果

Ca^ mobilization via ryanodine receptor type 2 in urinary bladder smooth muscle

Ca^<2 > 通过膀胱平滑肌中 2 型兰尼碱受体动员

• 发表时间: 2006
• 作者: Shingo; Hotta; Kozo; Morimura; Susumu; Ohya; Katsuhiko; Muraki; Hiroshi; Takeshima; Yuji; Imaizumi
• 通讯作者: Imaizumi

マウス大動脈平滑筋細胞におけるNa^+/Ca^交換輸送体の機能解析

小鼠主动脉平滑肌细胞Na^+/Ca^2+交换转运蛋白的功能分析

• 发表时间: 2006
• 作者: 村田 秀道

Changes in intermediate-conductance Ca^ -activated K^+ channel expression in smooth muscles of voltage-gated Ca^ channel β3 subunit null mice

电压门控Ca^2+通道β3亚基缺失小鼠平滑肌中电导Ca^2+激活K^+通道表​​达的变化

• 发表时间: 2005
• 作者: Kozo; Morimura; Susumu; Ohya; Hisao; Yamamura; Manabu; Murakami; Katsuhiko; Muraki; Kazuo; Nunoki; Teruyuki; Yanagisawa; Yuji; Imaizumi
• 通讯作者: Imaizumi

Two types of K^+ channel regulate cell proliferation and damage in bovine brain capillary endothelial cells

两种K^通道调节牛脑毛细血管内皮细胞的细胞增殖和损伤

• 发表时间: 2005
• 作者: Daiju; Yamazaki; Mineyoshi; Aoyama; Susumu; Ohya; Katsuhiko; Muraki; Kiyofumi; Asai; Yuji; Imaizumi
• 通讯作者: Imaizumi

Testosterone regulation of large-conductance Cat^-activated K^+ channel expression in ratvas deferens smooth muscle cells

睾酮对大鼠输精管平滑肌细胞大电导 Cat^2 激活 K^ 通道表达的调节

• 发表时间: 2005
• 作者: Akitoshi Ohn