Structural Insights into TRPV Channel Gating

项目摘要/摘要 瞬时受体电位(Trp)通道在人体生理中起着重要的作用，并促进必要的 离子(Na~+、Ca~(2+))透过质膜。这项建议的重点是针对暂时性的 受体电位香草素 2. (TRPV2)，它在心脏功能和免疫中发挥重要作用，并具有 被列入重要的抗肿瘤药物靶点名单。尽管如此，它仍然是研究最少的TRPV 在细胞和分子水平上的通道。我们建议使用冷冻-EM的组合， 电生理分析、定点突变和计算方法建立了详细的 对TRPV2通道门控机制的结构性理解。在当前的提案中，我们将重点关注 了解肌醇磷脂对TRPV2的调控，通过不同途径确定TRPV2的门控机制 并剖析了TRPV2与细胞骨架相互作用的分子机制。获取的信息 这些研究完成后，将有可能用于未来TRPV2特异性疗法的设计。

PROJECT SUMMARY/ABSTRACT Transient receptor potential (TRP) channels play significant roles in human physiology and facilitate essential ions' (Na+, Ca2+) permeation through the plasma membrane. The focus of this proposal is on the transient receptor potential vanilloid 2 (TRPV2), which plays an essential role in cardiac function and immunity, and has been placed on the list of important anti-tumor drug targets. Nevertheless, it remains the least studied TRPV channel at the cellular and molecular levels. We propose to use the combination of cryo-EM, electrophysiological analysis, site-directed mutagenesis, and computational methods to establish a detailed structural understanding of the mechanisms of TRPV2 channel gating. In this current proposal we will focus on understanding TRPV2 regulation by phosphoinositides, determine the mechanism of TRPV2 gating by diverse ligands and dissect the molecular mechanism of TRPV2 interaction with cytoskeleton. Information obtained upon completion of these studies will be potentially used for future design of TRPV2 specific therapeutics.