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

在兴奋性细胞中，如中枢神经系统神经元，当过度兴奋性和由此导致的过量钙内流发生时，细胞内钙稳态的负反馈调节系统起到防止钙霸权的作用。钙激活K+(Kca)通道的激活被认为是可兴奋细胞内钙离子负反馈调节的重要成分之一。本研究旨在阐明KCA通道活性调节的分子机制，并寻找调节疾病的变化。本课题的目标是寻找一些疾病中针对K_ca通道的分子种子。在研究期间，取得了以下进展。(1)牛血脑屏障来源的血管内皮细胞系上的小电导K_ca(SK)通道在内皮细胞中具有重要的功能作用；在ATP刺激下的增殖可能是由中枢星形胶质细胞释放的。(J…More BC，2006；J Pharmacol Sci，104,2007)。(2)在野生型和RyR2杂合子KO小鼠的膀胱平滑肌细胞中，兰诺定受体2(RyR2)通过肌浆网自发释放[Ca^&lt；2+&gt；火花，进而激活大电导Kca(BK)通道，对[Ca^&lt；2+&gt；]负反馈调节机制产生深刻影响。一系列证据表明，RyR2作为调节静息膜电位和肌张力以及兴奋-收缩偶联的关键分子，对膀胱的可控性有贡献(J Physiol，2007，J Pharmacol Sci，103,2007)。(3)研究发现潜在敏感的氧酮类染料是BK通道的有效开放剂。这是第一个合成的化合物，它对BK81具有开放特性，对BK62具有84个亚基的选择性。恶酚化合物可能是8亚基选择性BK通道开放剂的种子(Mol Pharmacol，2007)。(4)在低pH浴液中，自发性高血压大鼠(SHR)大动脉对激动剂的收缩反应明显增强。研究发现，SHR动脉平滑肌BK通道表达的增强及其对细胞外pH的敏感性是酸性pH诱导收缩增强的原因(Am J Physiol，2007)。较少

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