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，如中枢神经系统神经元，当过度兴奋和导致的过量Ca^2+内流发生时，细胞内Ca^2+稳态的负反馈调节系统起作用，以防止Ca^2+霸王。Ca^2+激活的K+（Kca）通道的激活是兴奋细胞内[Ca 2 ^+] i负反馈调节的重要组成部分。本研究旨在阐明Kca通道活性调控的分子机制，并探索其在疾病中的变化。本课题的目的是寻找某些疾病中以K_ca通道为靶点的分子种子。在研究期间取得了以下进展。(1)研究发现，来源于牛血脑屏障的血管内皮细胞系中的小电导K_ca（SK）通道在由星形胶质细胞释放的ATP刺激的内皮细胞增殖中具有重要的功能作用。（J ...更多信息 BC，2006; J Pharmacol Sci，104，2007）。(2)利用野生型和RyR 2杂合基因敲除小鼠膀胱平滑肌细胞，发现RyR 2通过肌浆网自发性Ca^2+释放（Ca^2+火花）和随后的大电导Kca（BK）通道激活，对[Ca^2+]负反馈调节机制产生深刻影响。一系列证据表明，RyR 2作为调节静息膜电位和肌肉紧张以及兴奋-收缩偶联的关键分子有助于膀胱大陆（J Physiol，2007，J Pharmacol Sci，103，2007）。(3)发现潜在敏感的oxonol染料作为有效的BK通道开放剂。它是第一个合成的化合物，显示出对BK 81和84亚基的开放性选择性超过BK 62。oxonol化合物可以是8亚基选择性BK通道开放剂的种子（Mol Pharmacol，2007）。(4)在低pH的水浴中，自发性高血压大鼠（SHR）离体大动脉对激动剂的收缩反应明显增强。发现SHR的动脉平滑肌中BK通道的增强表达及其对细胞外pH的敏感性是酸性pH诱导的收缩增强的原因（Am J Physiol，2007）。少

项目成果

Molecular and electrophysiological characteristics of K+ conductance sensitive to acidic pH in aortic smooth muscle cells of WKY and SHR

• DOI: 10.1152/ajpheart.00894.2005
• 发表时间: 2006-12-01
• 期刊: AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
• 影响因子: 4.8
• 作者: Kiyoshi, Hidekazu;Yamazaki, Daiju;Imaizumi, Yuji
• 通讯作者: Imaizumi, Yuji

Functional roles of Na^+/Ca^<2+> exchanger on the regulation of Ca^<2+> activated K^+ channels in vascular smooth muscle.

Na^/Ca^2交换器对血管平滑肌中Ca^2激活的K^通道调节的功能作用。

• 发表时间: 2006
• 作者: Kita;S.;伊豫田 拓也;村田 秀道;喜多 紗斗美;伊豫田 拓也;Kita S;Iyoda T;伊豫田 拓也;上原 吉就;喜多 紗斗美;喜多 紗斗美;伊豫田 拓也;リュウコウ;村田 秀道;渡邊 泰秀;Iwamoto T;Uehara Y;Kita S;Kita S;Iyoda T;Liu G;Murata H;Watanabe Y;喜多 紗斗美;Kita S;喜多紗 斗美;上原 吉就;Kita S;村田 秀道;堀田 真吾;古田 綾子;喜多 紗斗美;岩本 隆宏;喜多 紗斗美;Kita S.;Uehara Y.;Hotta S;Furuta A;Kita S;Iwamoto T;Kita S;Kita S;Uehara Y;Iwamoto T.;Kita S.;Niu CF.;Iwamoto T.;Matsui Y.;Kita S.;Kita S.;Watanabe Y.;Okabe K.;Inokuchi Y.;Zhang J.;Kita S.;Watanabe Y.;Iwamoto T;Kita S;Niu CF;Iwamoto T;Matsui Y;Kita S;Kita S;Watanabe Y;Okabe K;Inokuchi Y;Zhang J;Murata H
• 通讯作者: Murata H

Molecular mechanisms for BK channel activation by a novel opener, 12,14-dichlorodehydroabietic acid

新型开启剂 12,14-二氯脱氢松香酸激活 BK 通道的分子机制

• 发表时间: 2006
• 期刊: Journal of Pharmacology and Experimental Therapeutics 316(1)
• 作者: 今泉祐治;村木克彦;Morimura et al.;Sakamoto et al.
• 通讯作者: Sakamoto et al.

CNP activates a nonselective cation current in acutely isolated rat cardiac fibroblasts via NPR-C receptor mediated signaling

CNP 通过 NPR-C 受体介导的信号传导激活急性分离的大鼠心脏成纤维细胞中的非选择性阳离子电流

• 发表时间: 2007
• 期刊: J. Physiol.(Lond.) 580
• 作者: Miyazaki H;Shiozaki A;Niisato N;Marunaka Y.;Robert A. Rose
• 通讯作者: Robert A. Rose

脳血管内皮細胞において内向き整流性K^+チャネル(Kir2.1)の活性化により生じる過剰な過分極は細胞死を引き起こす

脑血管内皮细胞内向整流K^+通道（Kir2.1）激活引起的过度超极化导致细胞死亡。

• 发表时间: 2009
• 作者: Rose RA;Hatano N;Ohya S;Imaizumi Y;Giles WR;山崎 大樹
• 通讯作者: 山崎 大樹