High Throughput Screening for Specific Inhibitors and Modulators of A Novel Potas

描述(申请人提供)：高通量筛选与精神分裂症风险相关的新型钾通道KCNH2 3.1的特定抑制物和调节剂及其治疗摘要最近发现的KCNH2 3.1钾通道是HERG1钾通道的大脑选择性亚型，已被证明在精神分裂症患者的大脑中增加，这是精神分裂症出现的遗传风险因素，并影响神经细胞活动和大脑生理。由于许多现有的抗精神病药物与已知的Herg1通道结合，这种新的异构体的发现为开发无心脏副作用的抗精神病药物提供了一个潜在的新靶点。这项建议将使用现有的Herg1通道高通量铊通量分析来筛选表达新的Herg通道异构体的细胞系中的通道调制活性化合物。野生型HERG通道也将被平行筛选，以帮助确定KCNH2 3.1钾通道的选择性调节器。得到的化合物将在电生理学实验中得到验证。动物模型的可获得性将使未来能够在体内测试对记忆和与精神病有关的动物生理学的其他方面的影响。

DESCRIPTION (provided by applicant): High Throughput Screening for Specific Inhibitors and Modulators of A Novel Potassium Channel KCNH2 3.1 Associated with Risk for Schizophrenia and its treatment Abstract A recently discovered KCNH2 3.1 potassium channel, a brain selective isoform of the hERG1 potassium channel, has been shown to be increased in the brains of patients with schizophrenia, a genetic risk factor for the emergence of schizophrenia and to affect neuronal cell activity and brain physiology. Because many available antipsychotic drugs bind to know Herg1 channels, the discovery of the novel isoform offers a potential new target for the development of antipsychotic drugs without cardiac side effects. This proposal will use the available Herg1 channel high throughput thallium flux assay to screen compounds for channel modulating activity in a cell line expressing the novel isoform of the hERG channel. The wild type hERG channel will also be screened in parallel to help define the selective modulators of this KCNH2 3.1 potassium channel. The resulting compounds will be validated in electrophysiology experiments. The availability of animal models will allow future testing in vivo for effects on memory and other aspects of animal physiology linked with psychosis.