The antipsychotic drugs sertindole and pimozide block erg3, a human brain K+ channel
The antipsychotic drugs sertindole and pimozide block erg3, a human brain K+ channel
复制标题
DOI：
10.1006/bbrc.2001.5434
复制
发表时间：
2001-08-24
影响因子：
3.1
通讯作者：
Rampe, D
中科院分区：
文献类型：
--
作者：
Kang, JS;Chen, XL;Rampe, D
抗精神病药物舍替多尔和匹莫齐通过高亲和力阻断心脏K+通道HERG（人类乙醚相关基因；erg1）而延长心电图上的QT间期。我们希望测试这些药物是否也对相关的神经元K+通道erg3表现出高亲和力。编码erg3通道的cDNA从人脑文库中克隆而来。Northern的分析证实，相对于心脏、肝脏和肺部等其他组织，该通道定位于大脑。在大脑中，erg3在额叶和小脑中的表达量高于颞叶、顶叶和枕叶。在中国仓鼠卵巢细胞中，erg3的瞬时表达产生外向K+电流，该电流在-50 mV左右激活，并在正膜电位下产生大量瞬态成分。在-100 mV测量的内向尾电流以剂量依赖的方式被sertindole阻断，导致IC50值为43 nM。在低至3 nM的浓度下观察到显著的抑制作用。sertindole阻断erg3也表现出正的电压依赖性。Pimozide阻断erg3通道电流的IC50为103 nM，在浓度为10 nM及更高时具有显著的抑制作用。我们的结论是erg3可以被某些抗精神病药物如塞替多尔和匹莫齐阻断。抑制大脑中erg3或相关的K+通道可能有助于某些抗精神病药物的疗效/副作用。(C) 2001学术出版社。
The antipsychotic drugs sertindole and pimozide are known to prolong the QT interval on the electrocardiogram via a high affinity block of the cardiac K+ channel known as HERG (human ether-a-go-go-related gene; erg1). We wished to test whether these drugs also displayed high affinity for the related neuronal K+ channel erg3. The cDNA encoding erg3 channel was cloned from a human brain library. Northern analysis confirmed that the channel was localized to brain relative to other tissues including heart, liver and lung. Within the brain, erg3 was expressed in higher amounts in the frontal lobe and cerebellum relative to the temporal, parietal and occipital lobes. Transient expression of erg3 in Chinese hamster ovary cells produced outwardly directed K+ currents that activate at approximately -50 mV and produced a large transient component at positive membrane potentials. Inward tail currents measured at -100 mV were blocked in a dose-dependent fashion by sertindole resulting in an IC50 value of 43 nM. Significant inhibition was observed at concentrations as low as 3 nM. Block of erg3 by sertindole also displayed a positive voltage-dependence. Pimozide blocked erg3 channel currents with an IC50 of 103 nM and significant inhibition was noted at concentrations of 10 nM and higher. We conclude that erg3 can be blocked by certain antipsychotic drugs like sertindole and pimozide. Inhibition of erg3 or related K+ channels in the brain may contribute to the efficacy/side effect profiles of some antipsychotic drugs. (C) 2001 Academic Press.