Slo1 BK通道选择性滤器门控过程及调节机制的研究

门控机制是离子通道制离子通过和调控功能的关键问题。作为使用选择性滤器门控过程的Slo1 BK通道，目前其详细的门控过程和调节机制的分子基础仍然未得到系统、深入的阐释。本研究将综合应用膜片钳记录，分子动力学模拟，单分子FRET成像等不同技术，从不同时间和空间尺度阐明Slo1 BK通道选择性滤器门控的详细过程和调节的分子基础。通过本研究将回答如下关键问题：1.Slo1 BK通道选择性滤器片段中保守序列TVGYG如何通过特定构型变化调节钾离子和水分子的通导；2.Slo1 BK通道的主要功能结构域VSD，PGD，CTD和β亚基如何通过别构耦合机制调节选择性滤器片段的构型以及门控过程；3.哪些物理化学特性是影响功能结构域别构机制的关键因素。通过此项研究，我们将获得和通道门控过程及调节相关的重要功能和结构信息，并应用这些信息设计和制备新型Slo1 BK通道的激动剂作为治疗相关疾病的药物候选分子。

The ion channel gating mechanism is the key question about the research of ion channel modulation. The Slo1 BK channel, an important potassium channel, employ the selectivity filter (SF) gating, which is a major gating type. However, after several decades, there is still no fully answer how Slo1 BK channel use selectivity filter gating to control channel function and alternate the a lot physiological actives. In this research, we will combine multiple techniques, such as high-resolution patch clamp recording, molecular dynamic simulation, single molecular FRET, aim to resolve the underlie gating mechanisms. In this research, we will detect (1), what is key conformation of the conserved sequence “TVGYG” in Slo1 BK channel selectivity filter segment work for potassium ion and water molecular conductive; (2) how the major functional domain PGD, VSD, CTD and β subunits control the SF conformation via allosteric mechanism; (3) what is the major physicochemical properties contribute to functional domain allosteric coupling the functional-structural relationship. In use these findings, we will design and make new Slo1 BK channel activators as the drug candidates to treat some diseases, such as hypertension.