多肽抑制剂WGTx作用于Kir4.1通道的分子机制研究

内向整流钾通道Kir4.1对于调节神经元兴奋性至关重要，其表达或功能异常与多种中枢神经系统疾病的发生密切相关。Kir4.1通道抑制剂是用于研究通道结构-功能关系和生理病理功能的重要药理学工具。然而，现有Kir4.1通道抑制剂均为小分子，且在通道上的作用位点较为保守，因而对于具有新型作用模式的抑制剂有迫切需求。在前期研究中，我们从蜈蚣毒液中鉴定到了Kir4.1通道的首个多肽抑制剂WGTx。电生理研究发现WGTx电压依赖性地抑制Kir4.1通道电流的情况与小分子抑制剂截然相反，故推测WGTx作用于Kir4.1通道的模式不同于小分子抑制剂。基于此，本项目拟从毒素空间结构、作用模式和作用位点三个层面阐明WGTx与Kir4.1通道相互作用的分子机制，以证实上述推测。本项目的实施将直接促进我们对Kir4.1通道药理学的理解，同时为基于Kir4.1通道结构的药物设计和开发提供重要理论依据。

The inward rectifying potassium channel Kir4.1 plays a critical role in regulating neuronal excitability, and it is closely related to the occurrence of a variety of central nervous system diseases. Kir4.1 channel inhibitors are valuable pharmacological tools for investigating the structure-function relationships and physiological and pathological functions of channel. However, the existing Kir4.1 channel inhibitors are all small molecules with conservative binding sites on the channel, and there is an urgent need for novel inhibitors. In previous study, we identified the first peptide inhibitor of Kir4.1 channel, WGTX, from centipedes venom. And the electrophysiological results indicated that the voltage-dependent inhibition of Kir4.1 channel current by WGTX is very distinct from that of small molecule inhibitors. It is speculated that the mode of WGTX acting on Kir4.1 channel is distinct from that of small molecule. In the present study, we will try to explore the interaction molecular mechanism between WGTX and Kir4.1 channel through investigating the toxin spatial structure, action mode and binding sites. This study facilitates our understanding of the pharmacology of the Kir4.1 channel and lays a theoretical basis for drug design and development based on the Kir4.1 channel structure.