当前位置: X-MOL 学术Neurosci. Res. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Clozapine, nimodipine and endosulfan differentially suppress behavioral defects caused by gain-of-function mutations in a two-pore domain K+ channel (UNC-58)
Neuroscience Research ( IF 2.9 ) Pub Date : 2020-07-15 , DOI: 10.1016/j.neures.2020.07.006
Merve Kasap 1 , Donard S Dwyer 2
Affiliation  

Two-pore domain K+ channels (K2Ps) regulate the resting membrane potential in excitable cells and determine ease of depolarization. Gain-of-function (gf) mutations in one of these channels (unc-58) in C. elegans switch it to a Na+ conductance channel and cause tremors, paralysis and other defects. We hypothesized that it should be possible to identify drugs that corrected these defects in unc-58(gf) mutant animals by blocking or modulating the over-active channels. We examined dispersal of animals on food because the absence of effective forward locomotion is the most obvious defect. In addition, we quantified egg release over 24 h. Starting with a known inhibitor of mammalian K2Ps and directed structure-based screening, we evaluated numerous drugs in these assays. Loratadine, which inhibits human KCNK18, significantly improved movement as did methiothepin. We confirmed that endosulfan, a GABA-A receptor antagonist, corrected locomotion in the unc-58(gf) strains. Based on structural similarities to other hits, we found that clozapine, loxapine and amoxapine potently suppressed abnormal phenotypes. Curiously, nimodipine, a Ca++-channel blocker, dramatically improved movement and egg laying in unc-58(e665), but not unc-58(n495) animals. Molecular modeling provided initial insights into a possible basis for this difference based on the location of the e665 and n495 mutations. This research may lead to identification of novel K2P modulators and potential leads for drug discovery.



中文翻译:

氯氮平、尼莫地平和硫丹对双孔结构域 K+ 通道 (UNC-58) 中功能获得性突变引起的行为缺陷有不同的抑制作用

双孔域 K +通道 (K2Ps) 调节可兴奋细胞中的静息膜电位并确定去极化的难易程度。秀丽隐杆线虫中这些通道之一 ( unc-58 ) 中的功能获得 ( gf ) 突变将其转换为 Na +电导通道并导致震颤、瘫痪和其他缺陷。我们假设应该有可能识别出纠正unc-58(gf) 中这些缺陷的药物突变动物通过阻断或调节过度活跃的通道。我们检查了动物在食物上的分散,因为缺乏有效的向前运动是最明显的缺陷。此外,我们量化了 24 小时内的卵子释放量。从已知的哺乳动物 K2P 抑制剂和基于结构的定向筛选开始,我们在这些测定中评估了许多药物。抑制人类 KCNK18 的氯雷他定与甲硫磷素一样显着改善了运动。我们确认硫丹(一种 GABA-A 受体拮抗剂)可纠正unc-58(gf)菌株的运动。基于与其他命中的结构相似性,我们发现氯氮平、洛沙平和阿莫沙平有效抑制异常表型。奇怪的是,尼莫地平,一种 Ca ++通道阻断,大大提高了运动和鸡蛋产蛋UNC-58(e665) ,而不是UNC-58(n495)的动物。基于e665n495突变的位置,分子建模为这种差异的可能基础提供了初步见解。这项研究可能会导致新 K2P 调节剂的鉴定和药物发现的潜在线索。

更新日期:2020-07-15
down
wechat
bug