Selectivity filter gating in homomeric and heteromeric K+ channels

同聚和异聚 K 通道中的选择性滤光片门控

• 批准号: 329535048
• 负责人: Professor Dr. Thomas Baukrowitz
• 金额: --
• 依托单位: Physiologisches Institut
• 依托单位国家: 德国
• 项目类别: Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/329535048?language=en
• 关键词: Selectivity; filter; gating; homomeric; heteromeric

During the first funding period we discovered a novel pharmacological activation mechanism that provided new insight into the mechanism of selectivity filter (SF) gating in different classes of K+ channels (K2P channels, BK channels and hERG channels). We also characterized the unusual ion flux gating mechanism in TWIK channels and contributed to the identification of an allosteric inhibitor site in TASK-1/3 channels. The generated insight showcases the power of combining functional studies and MD simulations as the central purpose of this Research Unit. Here we propose to investigate the pharmacological and physiological mechanisms that control the (SF) gate in various K+ channels. The specific aims include (1) the characterization of the currently unexplored pharmacological and SF gating properties in heteromeric K2P channels as well as (2) in Slo2, TOK-1 and MthK channels, (3) the more global gating transitions in TREK-1 channels, (4) the role of the proximal C-terminus in K2P channel gating and (5) the coupling between SF and helix bundle crossing gate in various K+ channels. These investigations include electrophysiology (patch clamp and bilayer), mutagenesis (classical and unnatural amino acid) and fluorescence measurements on our side that will be comprehensively complemented by MD simulations performed by H. Sun (P3) and B. de Groot/W. Kopec (P5).

在第一个资助期间，我们发现了一种新的药理激活机制，为不同类别的K+通道(K2P通道、BK通道和HERG通道)的选择性过滤(SF)门控机制提供了新的见解。我们还表征了Twik通道中不寻常的离子通量门控机制，并有助于识别TASK-1/3通道中的变构抑制物位点。产生的洞察力展示了将功能研究和MD模拟结合起来作为本研究单位的中心目的的力量。在这里，我们建议研究在不同的K+通道中控制(SF)门的药理学和生理学机制。具体目标包括(1)表征目前未被探索的K2P异构体通道以及(2)Slo2、Tok-1和MthK通道的药理和SF门控特性，(3)Trek-1通道中更多的全局门控转变，(4)近端C-末端在K2P通道门控中的作用，以及(5)SF与各种K+通道中螺旋束交叉门之间的耦合。这些研究包括电生理学(膜片钳和双层)、诱变(经典和非天然氨基酸)和我们这边的荧光测量，这些将得到H.Sun(P3)和B.de Groot/W.Kopec(P5)进行的MD模拟的全面补充。