GIRK1-mediated inwardly rectifying potassium current suppresses the epileptiform burst activities and the potential antiepileptic effect of ML297
GIRK1-mediated inwardly rectifying potassium current suppresses the epileptiform burst activities and the potential antiepileptic effect of ML297
复制标题
GIRK1介导的内向整流钾电流抑制癫痫样爆发活动和ML297的潜在抗癫痫作用
DOI：
10.1016/j.biopha.2018.02.114
复制
发表时间：
2018-05-01
影响因子：
7.5
通讯作者：
Wang, Yun
中科院分区：
文献类型：
--
作者：
Huang, Yian;Zhang, Yuwen;Wang, Yun
G蛋白门控内向整流钾（GIRK）通道是中枢神经系统神经元兴奋性的重要抑制性调节因子，GIRK通道功能受损与癫痫易感性有关。然而，GIRK通道在癫痫发病机制中的动态机制尚不清楚。在本研究中，我们的研究结果表明，环噻嗪，一种强效惊厥药，剂量依赖性地增加癫痫样爆发活动，抑制巴氯芬诱导的GIRK电流。此外，选择性GIRK拮抗剂TPQ可显著降低总内整流钾（Kir）电流，增加神经元癫痫样活性。相比之下，ML297，一种强效和选择性的GIRK通道激动剂，逆转了环噻嗪诱导的GIRK电流下降和培养海马神经元兴奋性增加。进一步的研究表明，在抑制癫痫活动中发挥关键作用的是GIRK1，而不是GIRK2。最后，在匹罗卡品小鼠癫痫发作模型中，我们证明ML297显著抑制癫痫发作行为。综上所述，我们目前的研究结果表明，GIRK通道，特别是含有girk1的通道，参与癫痫活动，ML297具有潜在的抗癫痫作用。
G protein-gated inwardly rectifying potassium (GIRK) channels are important inhibitory regulators of neuronal excitability in central nervous system, and the impairment of GIRK channel function has been reported to be associated with the susceptibility of epilepsy. However, the dynamics of GIRK channels in the pathogenesis of epilepsy are still unclear. In this study, our results showed that cyclothiazide, a potent convulsant, dose dependently increased the epileptiform bursting activities and suppressed the baclofen induced GIRK currents. In addition, TPQ, a selective GIRK antagonist, significantly decreased the total inwardly rectifying potassium (Kir) current, and increased the neuronal epileptiform activities. In contrast, ML297, a potent and selective GIRK channel agonist, reversed the cyclothiazide induced decrease of GIRK currents and the increase of neuronal excitability in cultured hippocampal neurons. Further investigation revealed that GIRK1, but not GIRK2, played a key role in suppressing epileptic activities. Finally, in pilocarpine mice seizure model, we demonstrated that ML297 significantly suppressed the seizure behavior. In summary, our current results indicate that GIRK channels, especially GIRK1-containing channels, are involved in epileptic activities and ML297 has a potential antiepileptic effect.